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Ceramide

Ceramide is a family of bioactive sphingolipids that serve as fundamental building blocks of cell membranes and key regulators of cellular processes, consisting of a sphingoid base (typically sphingosine) linked via an amide bond to a fatty acid chain of varying lengths (C12 to ≥C26).^[1]^[2] These lipids are amphipathic, featuring hydrophilic hydroxyl groups and hydrophobic alkyl chains, which enable them to form organized lamellar structures in biological membranes.^[2] Ceramides are synthesized through multiple pathways, including de novo biosynthesis from serine and palmitoyl-CoA via serine palmitoyltransferase and ceramide synthases (CerS1–6), the salvage pathway recycling sphingoid bases and fatty acids, and hydrolysis of complex sphingolipids like sphingomyelin by sphingomyelinases.^[1]^[3] Their structural diversity arises from variations in chain length, saturation, and modifications such as hydroxylation, with very-long-chain (C20–C24) and ultra-long-chain (≥C26) forms predominant in mammalian tissues.^[1] In the skin, ceramides constitute approximately 50% of the lipids in the stratum corneum, forming a "brick-and-mortar" barrier with cholesterol and free fatty acids to prevent transepidermal water loss and protect against environmental stressors.^[2] Beyond structural roles, ceramides act as second messengers in signal transduction, influencing apoptosis, autophagy, inflammation, and cell proliferation by modulating membrane domains (e.g., ceramide-enriched platforms), binding effector proteins like protein phosphatases, and affecting mitochondrial function.^[1] Dysregulated ceramide levels are implicated in numerous diseases, including cancer (where elevated ceramides promote tumor cell death), metabolic disorders like obesity and insulin resistance (via impaired signaling), neurodegenerative conditions such as Alzheimer's disease (through neuronal apoptosis), and skin disorders like atopic dermatitis (due to barrier defects).^[1]^[3] Therapeutic strategies targeting ceramide metabolism, such as inhibitors of ceramide synthases or sphingomyelinases, hold promise for modulating these pathways in disease contexts.^[1]

Chemical Structure and Properties

Molecular Composition

Ceramides constitute a family of lipid molecules characterized by a sphingoid base, such as sphingosine or dihydrosphingosine, covalently linked to a fatty acid chain through an amide bond.^[2] This core structure forms the basis of sphingolipids, with the sphingoid base providing an amino alcohol backbone and the fatty acid contributing a hydrophobic tail.^[4] The sphingoid base is predominantly an 18-carbon (C18) chain, exemplified by sphingosine (trans-4-sphingenine, featuring a double bond between carbons 4 and 5 and hydroxyl groups at carbons 1 and 3) or dihydrosphingosine (sphinganine, the saturated analog).^[2] The attached fatty acid chain varies in length from C14 to C36, though most are very long chains (C20–C26) or ultra-long chains (>C26), often saturated but occasionally unsaturated, influencing the molecule's overall properties.^[2] Saturation levels and chain modifications, such as hydroxylation, further diversify ceramide species.^[5] A general structural representation for sphingosine-based ceramides is R–C(O)–NH–CH(CH₂OH)–CH(OH)–CH=CH–(CH₂)₁₂–CH₃, where R denotes the fatty acyl chain.^[4] Ceramides are classified into subclasses based on the sphingoid base and fatty acid type, including NP (non-hydroxy fatty acid with phytosphingosine base), NS (non-hydroxy fatty acid with sphingosine base), AP (α-hydroxy fatty acid with phytosphingosine base), and AS (α-hydroxy fatty acid with sphingosine base).^[2] In human skin, for instance, ceramide 2 belongs to the NS subclass and is a major component.^[6]

Physical and Chemical Properties

Ceramides exhibit an amphipathic character due to their molecular structure, featuring a hydrophobic acyl chain tail and a polar head group consisting of a sphingoid base with amide and hydroxyl functionalities.^[7] This duality enables ceramides to self-assemble into ordered structures such as bilayers or micelles in aqueous environments, facilitating their integration into lipid membranes.^[8] Long-chain ceramides, such as those with C18 acyl chains, are highly hydrophobic and insoluble in water, rendering them non-dispersible in aqueous solutions without solubilizing agents.^[9] In contrast, they readily dissolve in organic solvents like chloroform or chloroform-methanol mixtures, which are commonly used for lipid extraction and handling.^[10] Their critical micelle concentration (CMC) is notably low, often <10^{-7} M for C18 ceramides, reflecting their strong tendency to aggregate rather than remain monomeric in solution.^[11] In lipid membranes, ceramides promote the formation of gel phases at physiological temperatures, driven by their saturated acyl chains that enhance packing density.^[12] The main phase transition temperature increases with acyl chain length; for instance, C16-ceramide transitions at 90–93 °C, while C18-ceramide does so at 92 °C, often elevating the gel-to-fluid transition of coexisting phospholipids to near-body temperatures.^[12] Intermolecular hydrogen bonding between the amide groups in the head region further stabilizes these lamellar structures, particularly in skin barrier lipids, by forming extensive networks that resist water permeation.^[13] Recent studies from 2025 have elucidated variations in lateral packing among C18:0 ceramide subclasses at air-water interfaces using grazing-incidence X-ray diffraction.^[14] Sphingosine-based ceramides like CER[NS] adopt an orthorhombic phase with tilted chains (14.7° tilt angle) and tight packing (cross-sectional area ~20 Å²), promoting high stiffness (compression modulus 545 mN/m). In contrast, phytosphingosine-based subclasses such as CER[NP] and CER[AP] form oblique phases (tilt angles ~14–16°) with cross-sectional areas ~20 Å², stabilized by hydrogen bond networks, while dihydrosphingosine-based CER[NdS] exhibits a nontilted hexagonal arrangement (~20 Å²), influencing overall membrane rigidity and barrier function.^[14]

Biosynthesis Pathways

De Novo Synthesis

De novo synthesis represents the primary anabolic pathway for ceramide production, initiating from basic precursors in the endoplasmic reticulum (ER). This process builds ceramide from scratch, serving as a foundational mechanism for maintaining sphingolipid homeostasis in cells. Unlike recycling pathways, it directly incorporates amino acids and fatty acids into the sphingoid backbone, enabling net increases in ceramide mass particularly during cellular proliferation.^[15] The pathway unfolds through four sequential enzymatic steps in the ER. First, serine palmitoyltransferase (SPT), a heterodimeric complex, catalyzes the condensation of serine and palmitoyl-CoA to form 3-ketodihydrosphingosine (also known as 3-ketosphinganine), marking the committed and rate-limiting initiation. Second, 3-ketodihydrosphingosine reductase (KDSR) reduces this intermediate to sphinganine using NADPH as a cofactor. Third, one of six ceramide synthase isoforms (CerS1–6) acylates sphinganine with a fatty acyl-CoA to yield dihydroceramide; these isoforms exhibit substrate specificity, with CerS2 preferentially incorporating very long-chain fatty acids such as C24:0 to produce C24-ceramides. Finally, dihydroceramide desaturase 1 (DEGS1) introduces a 4,5-trans double bond using FAD as a cofactor, converting dihydroceramide to ceramide.^[15]^[16] Regulation of de novo synthesis occurs primarily at the SPT step, which is inhibited by ORMDL proteins (ORMDL1–3) that associate with the SPT complex in the ER membrane, sensing sphingolipid levels to prevent overaccumulation; the isoforms display varying sensitivities to ceramides, allowing fine-tuned homeostasis. CerS activity is further modulated by substrate availability and isoform expression, influencing the acyl chain diversity of resulting ceramides and thus their downstream functions, such as in membrane structure. Ceramide produced via this pathway can participate in signaling cascades, though its primary role here is biosynthetic.^[17]^[18]^[16] In growing or proliferating cells, de novo synthesis contributes substantially to total cellular ceramide levels, underscoring its importance for biomass expansion. Recent studies in 2025 have highlighted therapeutic potential, showing that targeted inhibition of hepatic de novo ceramide synthesis ameliorates metabolic dysfunction-associated steatohepatitis (MASH) by reducing ceramide accumulation and improving liver function.^[19]

Sphingomyelin Hydrolysis

Sphingomyelin hydrolysis serves as a key catabolic pathway for the rapid generation of ceramide, primarily mediated by sphingomyelinases that cleave the phosphocholine headgroup from sphingomyelin in cellular membranes.^[20] This process yields ceramide and phosphocholine, functioning in a manner akin to a phospholipase C reaction and enabling quick adjustments to ceramide levels in response to cellular cues.^[21] The primary enzyme involved is acid sphingomyelinase (ASMase), encoded by the SMPD1 gene, which exists in lysosomal and secreted forms; the lysosomal variant predominates in intracellular compartments, while the secreted form can act on extracellular or outer leaflet sphingomyelin.^[22] In contrast, neutral sphingomyelinase (NSMase), particularly the NSMase2 isoform, operates at the plasma membrane under neutral pH conditions.^[23] Activation of these enzymes occurs in response to stress signals, such as tumor necrosis factor-α (TNF-α), which triggers protein kinase C (PKC) pathways leading to ASMase phosphorylation and translocation. Specifically, PKCδ phosphorylates ASMase at serine 508, facilitating its trafficking from lysosomes to plasma membrane lipid rafts where sphingomyelin is enriched, thereby promoting localized ceramide production. NSMase2 activation similarly involves translocation to the plasma membrane upon TNF-α stimulation via PKC, contributing to ceramide accumulation in membrane domains.^[24] This rapid enzymatic response allows sphingomyelin hydrolysis to serve as a major contributor to the acute ceramide pool during signaling events in various cell types.^[25] Distinct isoforms like ASMase and NSMase2 exhibit preferences in substrate specificity, with both favoring sphingomyelin species containing saturated acyl chains prevalent in lipid rafts, though NSMase2 shows additional modulation by unsaturated fatty acids and phosphatidylserine.^[26] In central nervous system contexts, dysregulated ASMase activity and resultant ceramide elevation have been implicated in disorders such as Alzheimer's disease and ischemia, underscoring the pathway's role in stress-mediated pathology.^[27] The ceramide produced via this route participates in downstream signaling, including apoptosis and inflammation, though detailed mechanisms are addressed elsewhere.^[25]

Salvage Pathway

The salvage pathway represents a recycling mechanism for ceramide production, enabling cells to reutilize sphingoid bases and fatty acids derived from the degradation of complex sphingolipids, thereby complementing de novo synthesis by conserving cellular resources. This pathway primarily operates in acidic compartments, with key activities localized to lysosomes where degradation occurs, and extends to the Golgi apparatus for subsequent deacylation of short-chain ceramides and re-acylation to form mature ceramide species.^[28] The process begins with the hydrolysis of complex sphingolipids, such as glycosphingolipids (including gangliosides) or sphingomyelin, by lysosomal glycosidases, sialidases, and sphingomyelinases, yielding glucosylceramide as an intermediate. Glucosylceramide is then cleaved by the lysosomal enzyme glucosylceramide β-1→1-glucosidase (GBA, also known as acid β-glucosidase or GBA1) to generate free ceramide and glucose. An alternative route involves the degradation of galactosylceramide (GalCer), a major myelin lipid, by galactosylceramide β-galactosidase, directly producing ceramide and galactose.^[28]^[29]^[30] Within this pathway, acid ceramidase (ACER1) plays a dual role: it typically hydrolyzes ceramide to sphingosine and fatty acids, but under certain conditions, its reverse activity facilitates the formation of ceramide precursors from sphingosine and free fatty acids, contributing to net ceramide recovery despite ongoing catabolism. Overall, the salvage pathway efficiently recycles ceramide while preserving the diversity of acyl chain lengths from the original complex lipids, avoiding the need for new fatty acid synthesis.^[31]^[28] In differentiated cells, the salvage pathway dominates ceramide production, accounting for 50-90% of sphingolipid biosynthesis, with particularly high reliance in neural tissues such as the brain where it supports membrane maintenance and signaling. Defects in GBA activity, often due to mutations in the GBA1 gene, disrupt this pathway and lead to glucosylceramide accumulation, as seen in Gaucher disease, a lysosomal storage disorder. Recent studies have highlighted cell-type specific variations, showing that human induced pluripotent stem cell-derived neurons exhibit distinct salvage pathway kinetics and ceramide isoform profiles compared to glia, influencing toxicity responses to ceramide perturbations.^[28]^[32]^[33]

Metabolism and Catabolism

Sphingomyelin Synthase Reversal

Sphingomyelin synthases (SMSs) are key enzymes in ceramide metabolism that catalyze the reversible transfer of a phosphocholine headgroup from phosphatidylcholine (PC) to ceramide, yielding sphingomyelin (SM) and diacylglycerol (DAG). There are two main isoforms: SMS1, primarily localized in the Golgi apparatus, and SMS2, predominantly active at the plasma membrane.^[34] This bidirectional reaction, PC + ceramide ⇌ SM + DAG, allows for dynamic interconversion between ceramide and SM, helping to maintain lipid homeostasis in cellular membranes. The reversal of SMS activity generates net ceramide production from SM, particularly under conditions of low PC availability, which shifts the equilibrium toward ceramide and DAG formation. SMS2, due to its plasma membrane localization, is involved in rapid lipid adjustments during cellular signaling events, such as stress responses.^[35] This reversibility has been demonstrated in vitro, where SMS1 and SMS2 can hydrolyze SM to produce ceramide when PC substrate is limiting. This pathway serves as a secondary source of ceramide beyond de novo synthesis. In physiological contexts, SMS reversal helps maintain the SM-to-ceramide ratio in lipid rafts, stabilizing these membrane microdomains essential for protein clustering and signaling.^[36] Ceramide generated via this pathway can contribute to apoptosis signaling in immune regulation, though its primary metabolic role remains lipid interconversion.^[37]

Ceramidase-Mediated Breakdown

Ceramidases constitute a family of enzymes that catalyze the hydrolysis of ceramide into sphingosine and a free fatty acid, serving as the primary catabolic pathway for ceramide degradation in cells.^[38] This irreversible reaction, ceramide + H₂O → sphingosine + fatty acid, occurs at distinct subcellular locations and pH optima depending on the isoform, thereby regulating ceramide levels in response to cellular needs.^[39] In humans, five ceramidase isoforms have been identified: acid ceramidase (ASAH1), neutral ceramidase (ASAH2), and three alkaline ceramidases (ACER1, ACER2, ACER3).^[40] ASAH1, the lysosomal acid ceramidase, functions optimally at acidic pH (around 4.5) and hydrolyzes ceramides within the lysosome to prevent their accumulation.^[41] ACER1 and ACER3 are localized primarily to the endoplasmic reticulum (ER), with ACER3 also present in the Golgi apparatus, and exhibit alkaline pH optima (8.0–9.0), contributing to ceramide breakdown in early secretory compartments.^[42] ACER2 resides in the Golgi and lysosomal membranes, similarly favoring alkaline conditions.^[43] ASAH2, the neutral ceramidase, operates at neutral pH (7.0–8.0) and is associated with mitochondria and the plasma membrane, particularly in intestinal epithelia where it aids in dietary sphingolipid digestion.^[44] These isoforms collectively ensure compartmentalized control of ceramide turnover, with substrate specificities varying; for instance, ACER1 prefers very long-chain ceramides (C20:0–C24:0).^[42] The products of ceramidase activity—sphingosine and fatty acids—play distinct roles in cellular homeostasis. Sphingosine is rapidly phosphorylated by sphingosine kinases to form sphingosine-1-phosphate (S1P), a bioactive lipid that acts as a signaling molecule for cell migration, survival, and vascular integrity, or is exported from cells.^[45] Fatty acids are recycled into de novo lipid synthesis or β-oxidation, supporting energy metabolism and membrane biogenesis. This breakdown mitigates ceramide's pro-apoptotic and stress-inducing effects, restoring lipid balance. Ceramidase expression and activity are upregulated in conditions of elevated ceramide, such as during cellular stress or inflammation, to attenuate ceramide-mediated signaling.^[46] For example, ASAH1 activity increases in response to chemotherapeutic agents that elevate ceramide, promoting autophagy and cell survival.^[46] Mutations in ASAH1, leading to deficient acid ceramidase activity, cause Farber disease, a rare lysosomal storage disorder characterized by ceramide accumulation, resulting in painful lipogranulomas, joint deformities, and neurological impairment.^[47] By degrading signaling ceramides, ceramidases maintain sphingolipid rheostat balance, preventing excessive ceramide buildup that could trigger apoptosis or inflammation.^[38] Recent studies highlight the role of glial ceramidases, particularly ASAH1 and ACER3 in microglia and astrocytes, in neurodegeneration; for instance, increased expression of acid ceramidase and ACER3 in microglia is observed in Alzheimer's disease models, where ceramide accumulation contributes to neuronal loss.^[48] In Niemann-Pick disease, inhibiting acid ceramidase in glial cells normalizes lipid phenotypes and reduces pathology, suggesting therapeutic potential.^[49] Sphingosine generated in this pathway can be reutilized in the salvage pathway for ceramide resynthesis.^[38]

Cellular Functions

Role in Membrane Dynamics

Ceramides play a crucial structural role in cellular membranes by contributing to their organization and stability, particularly through the formation of ordered lipid domains. In the stratum corneum of the skin, ceramides are integral to the lamellar organization of the intercellular lipid matrix, where they assemble into stacked bilayers that form a permeability barrier against water loss and environmental stressors. This arrangement involves ceramides adopting an extended conformation, with their hydrophobic tails aligning to create a compact, crystalline structure that enhances barrier integrity.^[50] In other cellular contexts, such as the plasma membrane, ceramides participate in the formation of lipid rafts—cholesterol- and sphingolipid-enriched microdomains that facilitate membrane compartmentalization.^[51] A key biophysical property of ceramides is their ability to promote phase separation within lipid bilayers, leading to the generation of large ordered domains known as the liquid-ordered (Lo) phase. This process is driven by intermolecular hydrogen bonding between ceramide headgroups, which increases lipid packing density and reduces membrane fluidity compared to the surrounding liquid-disordered phase. Such phase behavior is particularly evident in model membranes where ceramide incorporation shifts the equilibrium toward more rigid, gel-like structures, influencing overall membrane dynamics.^[52] Ceramides interact closely with cholesterol and phospholipids to stabilize these bilayers; for instance, in skin lipids, cholesterol intercalates between ceramide molecules to reinforce the orthogonal packing of acyl chains, while phospholipids modulate the phase transitions. The human stratum corneum contains over 300 distinct ceramide species, which collectively optimize the barrier function through diverse chain lengths and saturations that fine-tune packing efficiency.^[53] In quantitative terms, ceramides constitute approximately 40-50% of the lipids in the stratum corneum, far exceeding their abundance in other membranes where they typically represent less than 5 mol%.^[54]^[55] Beyond organization, ceramides exert biophysical effects that alter membrane topology, including the promotion of positive membrane curvature essential for processes like vesicle fusion. By adopting a conical shape due to their small headgroup relative to the acyl chains, ceramides induce local bending in bilayers, facilitating the deformation required for membrane merging events. Recent studies using Langmuir monolayers have elucidated the packing behavior of C18 ceramides, revealing that their saturated acyl chains form highly ordered, hexagonal lattices at the air-water interface, which mimic the tight packing observed in cellular membranes and contribute to enhanced mechanical stability.^[56]^[5] These structural contributions provide a foundation for ceramide's involvement in domain-based signaling, though the primary emphasis here remains on their passive organizational roles.^[57]

Involvement in Cell Signaling

Ceramide functions as a lipid second messenger in eukaryotic cells, rapidly generated in response to various stimuli to regulate intracellular signaling cascades. Unlike structural lipids, ceramide's bioactive role involves on-demand production through enzymes such as sphingomyelinases and ceramide synthases, which modulate the activity of kinases and phosphatases to influence cell fate decisions.^[58]^[59] In signaling, ceramide exerts effects by inhibiting the kinase Akt (also known as protein kinase B) through dephosphorylation and activating protein phosphatase 2A (PP2A), which disrupts pro-survival complexes like Akt-Hsp90-eNOS. Additionally, ceramide promotes the formation of ceramide-rich platforms in the plasma membrane, enabling the clustering of receptors such as Fas and CD40 to amplify transmembrane signals. These platforms arise from ceramide's biophysical properties, which induce lateral phase separation and domain coalescence in lipid rafts.^[60]^[61]^[62] Ceramide signaling is prominent in stress responses, where it coordinates cellular adaptations to oxidative damage and nutrient deprivation, and in inflammation, where it drives cytokine production and immune cell activation. The functional outcomes depend on acyl chain length; for instance, C16-ceramide, synthesized by ceramide synthase 6, exhibits pro-apoptotic properties by enhancing mitochondrial permeability and ER stress. Ceramide is generated at key subcellular sites, including the Golgi apparatus via de novo synthesis, mitochondria through local synthases, and the plasma membrane by sphingomyelinase hydrolysis.^[63]^[59]^[64]^[65]^[66]^[67]^[62] Recent research highlights ceramide's role in T-cell immunity, with ceramide synthase 4 (CerS4) deficiency impairing T-cell proliferation and immune resolution in models of colitis and tumor progression, underscoring its importance in adaptive immunity.^[68]

Physiological Roles

Apoptosis Regulation

Ceramide plays a central pro-apoptotic role in programmed cell death by promoting mitochondrial outer membrane permeabilization and activating downstream effector cascades. In this process, ceramide accumulates in mitochondrial membranes, where it self-assembles into large, protein-permeable channels that facilitate the release of cytochrome c into the cytosol, thereby initiating the intrinsic apoptotic pathway.^[69] This channel formation is antagonized by anti-apoptotic proteins such as Bcl-2, which disassembles ceramide channels to prevent cytochrome c efflux, but elevated ceramide levels can overcome this inhibition through integrated stress responses that sensitize cells to apoptosis despite Bcl-2 presence.^[70]^[71] Key pathways linking ceramide to apoptosis involve activation of acid sphingomyelinase (ASMase) by tumor necrosis factor (TNF), which hydrolyzes sphingomyelin to generate ceramide at the plasma membrane and endolysosomes. This ceramide then translocates to mitochondria, activating initiator caspases such as caspase-9 and effector caspase-3, culminating in DNA fragmentation and cell demise.^[72] Notably, C16-ceramide, produced by ceramide synthase 6, is particularly potent in this context, as its specific elevation correlates with enhanced caspase activation and apoptosis induction in response to stress signals.^[73]^[74] In physiological contexts like embryonic development and targeted cancer therapies, ceramide levels typically rise 2- to 5-fold during apoptosis, serving as a tumor-suppressive signal that counters uncontrolled proliferation.^[75]^[76] For instance, radiation or chemotherapeutic agents elevate ceramide to drive apoptotic elimination of damaged cells, with C16-ceramide playing a determinant role in saturation-dependent pro-apoptotic effects.^[77] This regulation is counterbalanced by sphingosine-1-phosphate (S1P), an anti-apoptotic metabolite derived from ceramide breakdown, which promotes cell survival and shifts the ceramide/S1P rheostat toward proliferation when dominant.^[78] Recent hepatic studies demonstrate that inhibiting de novo ceramide synthesis ameliorates metabolic dysfunction-associated steatohepatitis (MASH) by suppressing hepatic lipid uptake, lipogenesis, steatosis, inflammation, and fibrosis in mouse models of metabolic stress.^[19]

Skin Barrier Maintenance

Ceramides constitute approximately 40-50% of the lipids in the stratum corneum, the outermost layer of the epidermis, where they play a pivotal role in maintaining the skin's protective barrier.^[79] These lipids, predominantly long-chain variants with fatty acid moieties ranging from C24 to C36, enable tight molecular packing within the intercellular space, forming a robust hydrophobic matrix that resists penetration by external substances.^[2] Among ceramide subtypes, esterified omega-hydroxy sphingosine (EOS) ceramides are particularly critical, as they facilitate covalent ω-hydroxyacyl linkages to structural proteins in the cornified envelope, anchoring the lipid lamellae and enhancing overall barrier integrity.^[80] In the stratum corneum, ceramides organize into multilayered extracellular lamellae that intermix with cholesterol and free fatty acids to create a permeability barrier, primarily preventing transepidermal water loss and maintaining hydration.^[81] This arrangement also contributes to antimicrobial defense, as ceramide-derived long-chain bases like sphingosine exhibit broad-spectrum activity against skin pathogens, reducing microbial colonization on the surface.^[82] Ceramides are primarily synthesized de novo by keratinocytes in the lower epidermal layers, with lamellar bodies transporting them to the intercellular spaces during terminal differentiation. The expression and synthesis of barrier ceramides are regulated by transcription factors such as peroxisome proliferator-activated receptor alpha (PPARα), which upregulates genes involved in ceramide production and keratinocyte differentiation to support barrier homeostasis.^[83] Deficiencies in ceramide levels impair this regulation, leading to delayed recovery of the skin barrier following disruption, as observed in models of epidermal injury where reduced ceramide content correlates with prolonged transepidermal water loss.^[84] Recent research from 2025 has highlighted the potential of early-life protein-bound skin ceramides as predictive biomarkers for atopic dermatitis, with lower levels in infancy associated with a higher risk of disease onset by age one year, offering opportunities for early intervention in barrier dysfunction.^[85]

Immune System Modulation

Ceramide synthase 4 (CerS4) plays a pivotal role in T-cell function by generating C18-ceramide, which supports T-cell activation, proliferation, cytokine production (such as IFN-γ and IL-2), and migration through enhancement of T-cell receptor signaling via Akt and NF-κB pathways.^[86] Deficiency in CerS4 specifically within T cells impairs these processes, leading to reduced T-cell infiltration and cytokine secretion, which attenuates graft-versus-host disease severity but prolongs inflammation and worsens colitis responses in dextran sulfate sodium (DSS) models, with increased mortality (62% versus 13% in wild-type) and higher neutrophil/macrophage infiltration.^[86]^[87] In macrophages, acid sphingomyelinase (ASMase)-derived ceramide promotes pro-inflammatory responses by facilitating the release of cytokines like IL-1β, particularly through exosome-mediated secretion triggered by stimuli such as oxidized low-density lipoprotein immune complexes, where ASMase activity increases 1.5-fold and is essential for IL-1β maturation via NLRP3 inflammasome activation.^[88]^[89] Ceramides contribute to immune modulation in autoimmunity and infection by enhancing T_H1/T_H17 differentiation, neutrophil infiltration, and pathogen-induced barrier disruption, as seen in models of multiple sclerosis and bacterial invasions like Pseudomonas. The ceramide-sphingosine-1-phosphate (S1P) axis balances pro- and anti-inflammatory effects, with ceramide driving NF-κB and MAPK-mediated inflammation while S1P promotes resolution through PI3K-Akt signaling and lymphocyte sequestration.^[89] Recent 2025 research highlights the complex roles of ceramide in T-cell function, including contexts where elevated ceramide levels, such as in aging, impair antitumor immunity by promoting mitophagy and mitochondrial dysfunction in peripheral T cells. In neuroinflammation, neuronal and glial cells exhibit distinct ceramide profiles—neurons with higher C18-ceramide and lower de novo synthesis versus glia (astrocytes and microglia) enriched in long-chain C24-ceramides and more responsive to synthesis inhibition—leading to differential inflammatory pathway activation, such as IL-17 signaling in glia.^[89]

Hormonal and Metabolic Signaling

Ceramides play a central role in the development of insulin resistance, particularly in the context of obesity, where their accumulation in metabolic tissues such as liver and adipose disrupts glucose homeostasis. In obese individuals, elevated ceramide levels in skeletal muscle and adipose tissue correlate with impaired insulin signaling, contributing to reduced glucose uptake.^[90] This accumulation is driven by increased de novo synthesis from dietary saturated fatty acids, which promotes ceramide production in the endoplasmic reticulum of hepatocytes and adipocytes.^[91] Specifically, ceramides inhibit the activation of Akt/protein kinase B (PKB), a key mediator of insulin-stimulated glucose transporter 4 (GLUT4) translocation to the cell membrane, thereby blocking glucose uptake in insulin-sensitive tissues.^[92] Seminal studies have demonstrated that ceramide generation alone is sufficient to suppress the insulin-PKB pathway in skeletal muscle cells, underscoring its direct antagonistic effect on metabolic signaling.^[93] Ceramides also modulate hormonal signaling involved in energy homeostasis, particularly through interactions with adipokines like leptin and adiponectin. Elevated ceramides in adipose tissue are associated with reduced adiponectin levels and signaling, which normally enhances insulin sensitivity and fatty acid oxidation; conversely, adiponectin receptors (AdipoR1 and AdipoR2) stimulate ceramidase activity to degrade ceramides and improve metabolic function.^[94] Leptin resistance in obesity further exacerbates ceramide buildup, linking hyperleptinemia to impaired lipid metabolism and insulin action.^[95] The enzyme ceramide synthase 6 (CerS6), which preferentially generates C14- to C16-ceramides, is upregulated in metabolic tissues like liver and adipose during obesity, promoting weight gain and dyslipidemia through enhanced de novo synthesis.^[96] This CerS6-dependent pathway integrates dietary lipid intake with systemic hormonal dysregulation, amplifying insulin resistance in key metabolic organs.^[97] Recent research highlights ceramides' role in type 2 diabetes progression and associated cardiovascular risks. In patients with type 2 diabetes, plasma C16:0 ceramide levels serve as a biomarker for atherosclerotic cardiovascular disease (ASCVD) risk, reflecting lipotoxicity that bridges metabolic dysfunction and vascular pathology.^[98] Studies from 2024 indicate that ceramide-driven lipotoxicity contributes to endothelial dysfunction and plaque formation in obesity-related diabetes, independent of traditional risk factors.^[99] These findings emphasize ceramides as pivotal mediators in the endocrine-metabolic axis, with implications for early intervention in cardiometabolic disorders.^[100]

Signaling Mechanisms

Effector Proteins and Pathways

Ceramide exerts its signaling effects through direct interactions with specific effector proteins, thereby modulating key cellular processes. One prominent interaction involves atypical protein kinase C ζ (PKCζ), where ceramide binds to the carboxyl-terminal domain of PKCζ, facilitating its activation and influencing pathways such as insulin signaling and apoptosis.^[101] Similarly, ceramide binds to cathepsin D, a lysosomal protease, activating it to promote downstream effects including mitochondrial dysfunction and cell death mechanisms.^[58] Additionally, ceramide facilitates the activation of mitogen-activated protein kinases (MAPKs) by reorganizing plasma membrane lipid rafts into ceramide-enriched platforms, which cluster signaling molecules and enhance MAPK phosphorylation in response to stress stimuli.^[62] Ceramide also engages protein phosphatase 2A (PP2A), forming ceramide-activated protein phosphatases (CAPPs) that dephosphorylate targets such as Akt, thereby inhibiting pro-survival signals and promoting stress responses like growth arrest.^[1] To diversify its signaling, ceramide is metabolized into ceramide-1-phosphate (C1P) by ceramide kinase or into sphingosine-1-phosphate (S1P) via ceramidase and sphingosine kinase; while ceramide typically induces pro-apoptotic effects, C1P and S1P often counter this by stimulating cell proliferation and survival through distinct receptor-mediated pathways.^[102] These conversions allow ceramide to fine-tune cellular outcomes depending on metabolic context. The signaling specificity of ceramide is influenced by acyl chain length. Short-chain ceramides, such as C2- and C6-ceramides, serve as cell-permeable analogs that mimic endogenous ceramide effects in experimental studies, rapidly entering cells to activate pathways like MAPK and PP2A without requiring de novo synthesis.^[103] In contrast, very long-chain ceramides (e.g., C24) primarily fulfill structural roles, stabilizing membrane domains and contributing to barrier integrity rather than direct signaling.^[104] Recent investigations highlight the role of acid sphingomyelinase (ASMase)-generated ceramide in facilitating viral entry through endocytosis. ASMase hydrolyzes sphingomyelin to produce ceramide, which alters membrane curvature and lipid raft dynamics, enabling viruses like SARS-CoV-2 to fuse with host cell membranes and internalize via endocytic pathways.^[105]

Intracellular Targets

Ceramide exerts its intracellular effects by targeting key enzymes involved in cell survival and signaling pathways. Specifically, ceramide inhibits the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, a critical regulator of cell growth and survival, thereby promoting apoptosis and growth suppression in various cell types.^[106] This inhibition occurs upstream of Akt activation, as overexpression of Akt or PI3K protects cells from ceramide-induced cell death.^[106] Additionally, ceramide activates protein phosphatase 2A (PP2A), known as ceramide-activated protein phosphatase (CAPP), which dephosphorylates target proteins to modulate signaling cascades such as those involving PKC and Raf-1.^[107] CAPP's activation requires specific ceramide structures, highlighting ceramide's role as a precise regulator of phosphatase activity in stress responses.^[108] At the organelle level, ceramide influences mitochondrial function by inducing the permeability transition pore (mPTP), leading to cytochrome c release and apoptosis initiation through a Bax-dependent mechanism.^[109] This process is calcium-dependent and sensitive to cyclosporin A, underscoring ceramide's direct impact on mitochondrial integrity during cell death signaling.^[110] In the endoplasmic reticulum (ER), ceramide triggers stress by activating the unfolded protein response (UPR), which disrupts protein folding homeostasis and promotes apoptosis via pathways involving CHOP and caspase-12.^[111] Ceramide-induced ER stress is linked to increased calcium release and ROS production, amplifying UPR signaling in stressed cells.^[112] Ceramide also interacts with lipid metabolism and membrane organization as intracellular targets. It serves as a substrate for glucosylceramide synthase (GlcT, also known as UGCG), which converts ceramide to glucosylceramide, the precursor for complex glycosphingolipids that modulate cell signaling and protect against ceramide toxicity.^[113] This glycosylation step is rate-limiting in sphingolipid biosynthesis and influences membrane fluidity.^[113] Furthermore, ceramide promotes the reorganization of lipid rafts by forming ceramide-enriched domains that displace cholesterol and sphingomyelin, altering platform stability and facilitating the clustering of signaling molecules like receptors and kinases.^[114] These domains can collapse rapidly, impacting apoptotic signaling through membrane curvature changes.^[114] Recent studies highlight cell-type-specific intracellular targets of ceramide, particularly in neuroprotection. In human iPSC-derived models, neurons and glia exhibit distinct ceramide isoform compositions and synthesis rates, with glial cells showing higher very long-chain ceramide levels that confer resilience to oxidative stress compared to neurons.^[32] Neuron-specific deletion of ceramide synthases CerS5 and CerS6, which produce C16-ceramide, reduces mitochondrial dysfunction and provides neuroprotection in models of neuroinflammation, such as experimental autoimmune encephalomyelitis, by limiting ceramide accumulation in neurons while preserving glial function.^[115] These differences suggest that modulating ceramide targets in glia versus neurons could enhance neuroprotective strategies.^[116]

Regulators and Inducers

Endogenous Regulators

Endogenous regulators of ceramide levels encompass a variety of intracellular enzymes, lipids, pathways, and stress-responsive mechanisms that fine-tune ceramide biosynthesis, hydrolysis, and degradation to maintain sphingolipid homeostasis. These factors operate within cellular compartments such as the endoplasmic reticulum (ER), Golgi apparatus, and lysosomes, responding to physiological signals to prevent excessive accumulation or depletion of ceramide, which could disrupt membrane integrity or signaling cascades.^[117] Key enzymatic regulators include ceramide synthases (CerS), which catalyze the acylation of sphinganine to form dihydroceramide in the de novo pathway. Conversely, the ORMDL proteins serve as negative regulators of serine palmitoyltransferase (SPT), the rate-limiting enzyme in de novo ceramide synthesis; ORMDL isoforms sense sphingolipid levels and inhibit SPT activity through direct interaction, establishing a feedback loop that downregulates ceramide biosynthesis when levels rise. This ORMDL-SPT mechanism is conserved across eukaryotes and ensures balanced sphingolipid production in the ER.^[118]^[119]^[117] Sphingolipid metabolites also modulate ceramide levels antagonistically. Sphingosine-1-phosphate (S1P), generated by sphingosine kinases (SphK1 and SphK2), opposes ceramide accumulation by inhibiting de novo biosynthesis; cytosolic S1P formed by SphK1 directly suppresses SPT activity, acting as a homeostatic sensor to limit ceramide-mediated stress responses. This S1P-ceramide rheostat influences cell survival and proliferation, with SphK1-derived S1P promoting anti-apoptotic signals in contrast to pro-apoptotic ceramide.^[120] Degradative pathways further control ceramide abundance. Autophagy limits excessive ceramide by sequestering and degrading sphingolipid-laden organelles or lipid droplets in the liver and other tissues; induction of autophagy in response to elevated de novo sphingolipid synthesis prevents ceramide overload, highlighting its role in sphingolipid catabolism and cellular adaptation. Hormonal signals, such as insulin, suppress de novo ceramide synthesis through insulin receptor-mediated pathways that inhibit SPT and promote ceramide conversion to complex sphingolipids like sphingomyelin, thereby enhancing insulin sensitivity and glucose homeostasis.^[121]00142-8) Stress contexts activate ceramide generation via sphingomyelinase trafficking. Ultraviolet (UV) radiation induces acid sphingomyelinase (ASMase) translocation from lysosomes to the plasma membrane, where it hydrolyzes sphingomyelin to produce ceramide-enriched platforms that facilitate signaling for apoptosis or repair in keratinocytes. Similarly, hypoxia triggers ASMase activation and trafficking, elevating ceramide levels in cardiac myocytes and endothelial cells to mediate adaptive responses like vascular tone regulation, though prolonged hypoxia can lead to ceramide-driven injury. These mechanisms underscore how endogenous stressors dynamically modulate ceramide to balance survival and pathological outcomes.^[122]^[123]

Exogenous Inducers

Exogenous inducers of ceramide encompass a range of external stimuli that elevate cellular ceramide levels primarily through activation of sphingomyelin hydrolysis or de novo synthesis pathways. These agents include cytokines, chemotherapeutic drugs, environmental stressors, and viral infections, each engaging specific enzymes such as neutral sphingomyelinase (NSMase) or acid sphingomyelinase (ASMase) to generate ceramide as a signaling lipid.^[124] Cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) are potent inducers of ceramide production via sphingomyelinase activation. TNF-α stimulates both NSMase and ASMase, leading to rapid hydrolysis of sphingomyelin into ceramide in various cell types, including endothelial and immune cells.^[125] Similarly, IL-1β upregulates secretory sphingomyelinase in a time- and dose-dependent manner, resulting in the formation of specific ceramide species that contribute to inflammatory signaling.^[124] These cytokine-induced ceramide elevations often occur within minutes to hours, amplifying downstream pathways such as apoptosis and inflammation.^[126] Chemotherapeutic agents also induce ceramide accumulation, often as a mechanism underlying their cytotoxic effects. Daunorubicin, an anthracycline used in leukemia treatment, triggers de novo ceramide synthesis in leukemic cell lines like U937 and HL-60, where it activates serine palmitoyltransferase to elevate long-chain ceramides and promote apoptosis at concentrations that induce cell death.^[127] Fenretinide, a synthetic retinoid analog, stimulates ceramide production through redox-sensitive mechanisms involving de novo synthesis in breast cancer cells, enhancing ceramide-mediated growth inhibition.^[128] Environmental stressors, particularly ultraviolet (UV) radiation and oxidative stress, activate ceramide generation via hydrolytic and synthetic routes. UV radiation, including UVA and UVB, induces neutral and acidic sphingomyelinases in keratinocytes, leading to sphingomyelin hydrolysis and ceramide accumulation starting as early as 15 minutes post-exposure; UVB additionally upregulates de novo synthesis through increased ceramide synthase activity.^[122] Oxidative stress, such as from hydrogen peroxide (H2O2), promotes ceramide formation by phosphorylating and activating sphingomyelinases on cellular membranes, contributing to stress kinase activation in fibroblasts and other cells.^[129] These inductions often result in ceramide-rich platforms that facilitate transmembrane signaling.^[130] Viral infections represent a more recent area of focus for exogenous ceramide induction, particularly through ASMase-mediated mechanisms. SARS-CoV-2 activates ASMase on host cell surfaces, elevating ceramide levels to facilitate viral entry and replication; this process supports infection in respiratory epithelial cells and has been observed in severe COVID-19 cases as of 2025.^[131] Inhibition of ASMase reduces ceramide accumulation and impairs viral propagation, highlighting its role in pathogenesis.^[132] The dose and temporal dynamics of induction significantly influence ceramide pathway outcomes, with acute exposures typically favoring rapid hydrolysis via sphingomyelinases, while chronic or higher-dose stimuli shift toward sustained de novo synthesis. For instance, low-dose TNF-α induces transient ceramide peaks via NSMase for pro-survival signaling, whereas higher or prolonged doses activate ASMase for apoptotic responses in a cell-type-specific manner.^[133] This differential activation underscores the context-dependent effects of exogenous inducers on ceramide-mediated cellular responses.^[134]

Associated Diseases

Dermatological Disorders

Ceramide dysregulation in the stratum corneum plays a central role in various dermatological disorders by compromising the skin's permeability barrier, leading to increased transepidermal water loss (TEWL) and heightened susceptibility to irritants and allergens.^[135] In these conditions, alterations in ceramide chain length and subclass distribution disrupt the organized lipid lamellae essential for barrier integrity.^[136] In atopic dermatitis (AD), reduced levels of long-chain ceramides, particularly omega-hydroxy sphingosine (POS) species, are associated with impaired barrier function and increased skin permeability.^[137] These deficiencies contribute to disease development, especially in nonatopic forms of AD, where early-life reductions in protein-bound POS ceramides predict higher risk.^[137] Ceramide profiles in AD lesional skin show a shift toward shorter-chain fatty acids, exacerbating inflammation and dryness.^[54] By 2025, stratum corneum ceramide levels have emerged as potential biomarkers for monitoring AD severity and predicting flares, alongside pH dysregulation.^[138] Psoriasis involves elevated short-chain ceramides in lesional skin, which correlate with disrupted lipid organization and reduced barrier recovery.^[139] These short-chain species, often with fatty acid lengths below C34, promote pro-inflammatory signaling by altering ceramide metabolism and increasing cytokine production in keratinocytes.^[140] The imbalance, including decreased average ceramide chain length, contributes to the hyperproliferative and inflamed phenotype observed in psoriatic plaques.^[141] Netherton syndrome, caused by loss-of-function mutations in the SPINK5 gene encoding the LEKTI protease inhibitor, results in unchecked serine protease activity that impairs ceramide processing in the epidermis.^[142] This leads to reduced β-glucocerebrosidase activity and elevated acid sphingomyelinase, causing decreased levels of long-chain and acyl-ceramides (e.g., [EO] subclasses) while increasing short-chain ceramides (e.g., [AS] and [NS] subclasses).^[136] The resulting ceramide abnormalities, more severe in scaly erythroderma subtypes, directly contribute to profound barrier defects and elevated TEWL.^[142] Skin aging is characterized by declining ceramide levels, particularly in the stratum corneum, which correlates with increased TEWL and xerosis.^[84] This age-related reduction disrupts lipid bilayer formation, leading to drier, more fragile skin prone to environmental damage.^[143] Ceramide profiling via mass spectrometry has become a diagnostic tool for these disorders, enabling quantification of subclass distributions and chain lengths from tape-stripped stratum corneum samples.^[144] Liquid chromatography-mass spectrometry (LC-MS) methods allow for subclass-specific analysis, revealing diagnostic patterns such as reduced long-chain ceramides in AD and elevated short-chain species in psoriasis.^[145] These profiles support non-invasive assessment of barrier dysfunction and disease severity.^[146]

Metabolic and Cardiovascular Diseases

Ceramide accumulation plays a central role in the pathogenesis of metabolic and cardiovascular diseases, primarily through its promotion of insulin resistance and vascular inflammation. Elevated levels of specific ceramide species, such as C16:0 and C18:0, are associated with impaired glucose homeostasis and increased cardiovascular risk, driven by disruptions in key signaling pathways.^[147]^[148] In type 2 diabetes, plasma and tissue levels of C16:0 and C18:0 ceramides are elevated and positively correlate with HbA1c levels, reflecting poor glycemic control.^[148] These ceramides inhibit insulin signaling by impairing Akt activation, leading to reduced glucose uptake in insulin-sensitive tissues.^[149]^[150] In obese subjects with type 2 diabetes, higher concentrations of C18:0 ceramides are inversely associated with insulin sensitivity, exacerbating hyperglycemia.^[149] Ceramides contribute to atherosclerosis by promoting endothelial inflammation and foam cell formation. In vascular endothelial cells, ceramide generated by acid sphingomyelinase activates proinflammatory signaling pathways, enhancing monocyte adhesion and lesion development.^[151] Ceramides also facilitate LDL aggregation and uptake by macrophages, driving the transformation into foam cells that accumulate in plaques.^[152] This process is amplified in hyperlipidemic conditions, where ceramide enrichment in atherosclerotic lesions sustains chronic inflammation.^[153] In metabolic dysfunction-associated steatotic liver disease (MASLD), hepatic de novo ceramide synthesis is upregulated, contributing to lipid accumulation and steatosis. Inhibition of this pathway reduces liver lipid content and ameliorates steatosis in preclinical models.^[91] A 2025 study demonstrated that targeted inhibition of hepatic ceramide synthesis attenuates steatosis and fibrosis in MASLD, highlighting its therapeutic potential.^[19] Plasma ceramides serve as biomarkers for cardiovascular disease (CVD) risk, with the CER-16:0/24:0 ratio independently predicting major adverse events.^[154] Elevated CER-16:0 relative to CER-24:0 is associated with increased fatal CVD risk in patients with metabolic syndrome.^[155] These effects are mediated via protein phosphatase 2A (PP2A)/Akt signaling in adipocytes and vascular cells. In adipocytes, ceramides activate PP2A, leading to Akt dephosphorylation and insulin resistance.^[156] In endothelial cells, ceramide-induced PP2A disrupts the eNOS-Akt complex, impairing vasodilation and promoting dysfunction.^[61] Ceramide plays a significant role in neurodegeneration, where its elevation contributes to disease pathology. In Alzheimer's disease, amyloid-beta (Aβ) oligomers and hyperphosphorylated tau induce acid sphingomyelinase (ASMase) activity, leading to increased ceramide levels in neurons and promoting neuroinflammation and cell death.^[157] Similarly, Gaucher disease arises from mutations in the GBA1 gene encoding glucocerebrosidase, which normally hydrolyzes glucosylceramide to ceramide; these defects result in glucosylceramide accumulation and altered ceramide homeostasis, exacerbating lysosomal dysfunction and neuronal damage.^[158] In Parkinson's disease, ceramide interacts with α-synuclein, facilitating its aggregation and propagation via extracellular vesicles, thereby worsening proteinopathy and dopaminergic neuron loss.^[159] Recent findings also link central nervous system ASMase activity to depression, with elevated levels in 2025 studies correlating to impaired hippocampal neurogenesis and mood dysregulation.^[160] In cancer, ceramide exhibits a dual role, acting as a pro-apoptotic agent in therapeutic contexts while sometimes promoting tumor progression. For instance, in glioma treatment, exogenous C6-ceramide induces apoptosis in glioblastoma cells by disrupting mitochondrial function and activating death pathways, positioning it as a potential chemotherapeutic adjunct.^[161] Conversely, in metastasis, ceramide can drive autophagy-dependent survival mechanisms; in pancreatic cancer, ceramide signaling via PI4KA/AKT enhances autophagic flux, facilitating tumor cell migration and metastatic outgrowth.^[162] This context-dependent behavior underscores ceramide's influence on cancer hallmarks like invasion and therapy resistance. Differences in ceramide composition between glial cells and neurons impact brain function, particularly myelin integrity. A 2024 study revealed that human induced pluripotent stem cell-derived neurons exhibit higher rates of C16- and C18-ceramide synthesis compared to glia, with variations in isoform profiles affecting cellular toxicity and lipid raft formation essential for myelination.^[32] These disparities contribute to demyelination in disorders like multiple sclerosis, where altered ceramide levels in oligodendrocytes disrupt sheath stability.^[32] Ceramide's effects are highly context-dependent, exemplifying its dual nature across physiological and pathological states. For example, C18-ceramide provides protective benefits in immunity by modulating T-cell receptor signaling to enhance antiviral responses, yet it exerts neurotoxic effects in neurons by inducing endoplasmic reticulum stress and apoptosis.^[163]^[32] This bifunctionality highlights the need for targeted interventions that exploit ceramide's pro-death roles in disease while mitigating its detrimental impacts.

Therapeutic Applications

Ceramide-Based Treatments

Ceramide-based treatments primarily involve the direct topical or systemic application of ceramides or their derivatives to restore skin barrier function, induce apoptosis in diseased cells, or support tissue repair. In atopic dermatitis (AD), where ceramide levels in the stratum corneum are significantly reduced, leading to impaired barrier integrity and increased transepidermal water loss (TEWL), topical formulations containing ceramides have demonstrated efficacy in clinical settings. For instance, ceramide-dominant emollients, such as those incorporating ceramide NP (N-palmitoylphytosphingosine) and ceramide AP (α-hydroxy-N-palmitoylphytosphingosine), applied twice daily for four weeks, reduced SCORAD scores by up to 50% and improved hydration by decreasing TEWL by 20-30% compared to vehicle controls.^[135]^[164]^[165] These treatments work by replenishing the lipid matrix, mimicking the skin's natural lamellar structure, and normalizing the ceramide profile to a healthy phenotype.^[166] Short-chain ceramide analogs, such as C6-ceramide, have been explored for anticancer applications due to their pro-apoptotic effects. Encapsulated in nanoliposomes or graphene oxide nanoparticles, C6-ceramide enhances cellular uptake and selectively induces caspase-dependent apoptosis in cancer cells, including breast and osteosarcoma lines, while sparing healthy cells. In preclinical models, nanoliposomal C6-ceramide combined with chemotherapeutic agents like doxorubicin has shown enhanced tumor regression and boosted anti-tumor immune responses via T-cell activation.^[167]^[168]^[169] Beyond AD and oncology, ceramides support wound healing and anti-aging in cosmetic and therapeutic contexts. Topical C24-ceramide lipid nanoparticles accelerate re-epithelialization in full-thickness wounds by promoting keratinocyte proliferation and collagen deposition, accelerating wound closure in murine models. In anti-aging formulations, ceramides fortify the skin barrier against environmental stressors, reducing fine lines and improving elasticity through sustained hydration and anti-inflammatory effects.^[170]^[171]^[54] Despite these benefits, challenges in ceramide-based treatments include poor aqueous solubility and bioavailability, which limit penetration and stability in formulations. To address this, pseudo-ceramides—synthetic analogs like pseudoceramide-1—serve as cost-effective alternatives, mimicking ceramide structure to restore barrier function with comparable efficacy in reducing dryness and irritation in AD patients.^[81] As of 2025, emerging research highlights ceramide derivatives for predictive and targeted skin disease management. The ceramide NP/NS ratio in the stratum corneum has been validated as a biomarker for early detection of barrier disruption in conditions like AD, enabling personalized treatment strategies that prevent flares. Additionally, novel ceramide-infused regimens have shown sustained symptom reduction in inflammatory dermatoses, improving quality of life metrics by 30-50%.^[172]^[54]^[173]

Synthesis Inhibitors and Analogs

Synthesis inhibitors target key enzymes in the de novo biosynthesis pathway of ceramides, such as serine palmitoyltransferase (SPT), acid sphingomyelinase (ASMase), and ceramide synthases (CerS), to reduce elevated ceramide levels implicated in disease progression. These inhibitors, along with structural analogs, offer pharmacological tools for modulating sphingolipid metabolism, particularly in metabolic, inflammatory, and oncogenic contexts. By blocking ceramide accumulation, they aim to mitigate insulin resistance, apoptosis dysregulation, and membrane signaling disruptions without directly supplementing ceramides. Serine palmitoyltransferase (SPT), the rate-limiting enzyme in ceramide de novo synthesis, is inhibited by natural products like myriocin and lipoxamycin, which exhibit high selectivity and potency. Myriocin, derived from fungi, potently suppresses SPT activity (IC₅₀ ≈ 20 pM), thereby reducing de novo ceramide biosynthesis and demonstrating benefits in improving lipid metabolism and glucose homeostasis in models of insulin resistance and metabolic syndrome.^[174] Lipoxamycin, another fungal-derived inhibitor, similarly targets SPT with nanomolar potency (IC₅₀ = 21 nM), showing potential in immunosuppression by limiting sphingolipid-dependent immune cell activation.^[175] These compounds have been instrumental in preclinical studies elucidating ceramide's role in metabolic disorders, though their clinical translation is limited by off-target effects on fungal and mammalian SPT homologs. Acid sphingomyelinase (ASMase) inhibitors, such as the tricyclic antidepressants amitriptyline and imipramine, reduce ceramide generation from sphingomyelin hydrolysis, particularly in the central nervous system. Amitriptyline inhibits ASMase activity at therapeutic concentrations, lowering brain ceramide levels and contributing to antidepressant effects in major depression models by alleviating ceramide-mediated neuroinflammation and synaptic dysfunction.^[176] Imipramine similarly suppresses ASMase, with lasting reductions in ceramide observed in peripheral blood mononuclear cells, supporting its role in modulating stress-induced ceramide signaling. Beyond psychiatric applications, functional inhibitors of ASMase (FIASMAs), including these agents, have shown promise in viral therapies; for instance, amitriptyline blocks ceramide-enriched membrane platforms essential for SARS-CoV-2 entry, reducing infection severity in preclinical evaluations as of 2021, with ongoing interest in 2025 for emerging viral threats.^[177] Ceramide synthases (CerS), which acylate sphinganine to form specific ceramide species, are targeted by isoform-selective inhibitors for cancer therapy, with CerS1 modulation particularly relevant in prostate cancer. Isoform-specific CerS inhibitors, such as ST1072 for CerS4/CerS6 and novel selective agents for CerS1, allow precise modulation of ceramide chain lengths and their downstream signaling in tumorigenesis.^[178] In prostate cancer, erianin promotes anti-tumor mechanisms by elevating pro-apoptotic C16 ceramides through induction of endoplasmic reticulum stress, disrupting cancer cell survival pathways.^[179] Structural analogs like fumonisin B1, a mycotoxin, potently block multiple CerS isoforms by mimicking sphingoid base substrates, leading to disrupted ceramide homeostasis and toxicity in high-dose exposures. Therapeutically, fumonisin B1-inspired CerS inhibition has demonstrated benefits in diabetes and cardiovascular disease models by lowering C16:0 ceramide levels, improving insulin sensitivity, and reducing vascular inflammation.^[180] In clinical contexts, inhibitors of hepatic de novo ceramide synthesis have advanced toward metabolic liver diseases like non-alcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated steatohepatitis (MASH). A 2025 study demonstrated that liver-targeted SPT inhibition via Sptlc2 knockdown suppresses ceramide accumulation, ameliorating steatosis, inflammation, and fibrosis in MASH mouse models, highlighting the pathway's therapeutic potential.^[19] As of late 2025, Phase II trials for ceramide synthesis inhibitors in NAFLD/MASH remain emerging, with preclinical data supporting their evaluation for hepatic interventions and broader FIASMA repurposing efforts underway for related metabolic indications.

Ceramide in Microorganisms

Occurrence in Bacteria

Ceramides are notably rare among prokaryotes, being absent in the vast majority of bacteria due to the evolutionary divergence of sphingolipid metabolism from eukaryotic pathways. However, they have been identified in select anaerobic species, such as Bacteroides fragilis, where free ceramides occur at high concentrations in chloroform-methanol extractable lipids, suggesting a salvage-like incorporation mechanism rather than de novo synthesis in all cases.^[181] Recent microbial diversity studies, including a 2024 analysis of Acidobacterium Solibacter usitatus, have expanded this list to include soil-dwelling bacteria, revealing ceramide presence in phyla previously thought devoid of sphingolipids.^[182] Bacterial ceramide biosynthesis represents a case of convergent evolution, employing enzymes non-homologous to those in eukaryotes and often utilizing sphinganine (dihydrosphingosine) analogs as backbone precursors. Key steps involve bacterial serine palmitoyltransferase (Spt), ceramide synthase (CerS), and reductase (CerR) enzymes, forming a complete pathway with six proteins identified across diverse genera like Caulobacter and Bacteroides.^[183] This prokaryotic route contrasts with the eukaryotic de novo pathway by lacking canonical acyl-CoA-dependent elongases and instead relying on distinct lipid transfer mechanisms for membrane integration.^[184] In bacteria where ceramides occur, they primarily contribute to membrane stabilization, particularly in extremophiles adapting to environmental stresses like varying pH, temperature, and oxygen levels, as observed in Acidobacterium species.^[182] Additionally, ceramides facilitate signaling in symbiotic interactions, such as in gut-associated Bacteroides thetaiotaomicron, where they modulate host anti-inflammatory responses via invariant natural killer T cell activation and integration into mammalian ceramide pools to maintain intestinal homeostasis.^[185] In pathogenic contexts, Helicobacter pylori leverages ceramide-mediated host signaling for virulence, though direct bacterial production remains under investigation; related studies highlight ceramide's role in bacterial adhesion and inflammatory modulation during infection.^[186] A 2024 study on Bacteroides-derived ceramides further underscores their impact on host vascular senescence, linking microbial sphingolipids to broader symbiotic dysregulation.^[187]

Ceramide Phosphoethanolamine

Ceramide phosphoethanolamine (CPE) is a sphingolipid composed of a ceramide backbone—a sphingoid base linked to a fatty acid via an amide bond—capped with a phosphoethanolamine headgroup, making it structurally analogous to sphingomyelin but with ethanolamine replacing choline.^[188] This headgroup confers zwitterionic properties to the molecule, contributing to its integration into lipid bilayers.^[189] CPE is a prominent sphingolipid in certain bacterial phyla, particularly within the Bacteroidetes group, including genera such as Bacteroides, Porphyromonas, and Prevotella, where it serves as a dominant component of the membrane lipidome.^[188] In these species, CPE constitutes a significant proportion of total membrane lipids, often comprising around 10% or more of the overall lipid content, with levels reaching up to 70% in total lipid extracts of some strains.^[185] While primarily associated with Bacteroidetes, trace occurrences have been noted in other prokaryotes, though not prominently in Helicobacter species.^[188] In bacterial membranes, CPE plays key roles in maintaining structural integrity and physiological functions, including support for ion balance through its amphipathic nature and contribution to membrane fluidity.^[190] Its presence enhances bacterial resistance to host-derived phospholipases, as sphingolipids like CPE are poor substrates for many eukaryotic phospholipase enzymes, thereby aiding pathogen persistence in host environments.^[191] Additionally, in Bacteroidetes, CPE is essential for cellular signaling and adaptation to environmental stresses.^[185] Biosynthesis of CPE in bacteria begins with de novo ceramide formation via serine palmitoyltransferase (SPT), which condenses L-serine and an acyl-CoA to produce 3-ketodihydrosphingosine, followed by reduction and N-acylation steps to yield ceramide.^[192] The phosphoethanolamine headgroup is then attached to ceramide by a CDP-ethanolamine:ceramide phosphoethanolamine synthase (CPE synthase), transferring the phosphoethanolamine moiety from CDP-ethanolamine, analogous to mechanisms observed in eukaryotic systems but adapted for prokaryotic pathways.^[190]^[188] In the context of the gut microbiome, Bacteroidetes-derived CPE influences host physiology by modulating intestinal homeostasis and immune responses, with deficiencies linked to dysbiosis and elevated inflammation markers such as IL-6 and MCP-1.^[192] Recent studies have highlighted its dual role: promoting anti-inflammatory pathways via outer membrane vesicle delivery while, in excess from certain pathobionts like Bacteroides fragilis, exacerbating colitis by suppressing IL-22 production and epithelial integrity, as evidenced in 2024 models of inflammatory bowel disease.^[193]

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Ceramidase - an overview | ScienceDirect Topics
Ceramidase is an enzyme that catalyzes the hydrolysis of ceramide into sphingosine and fatty acid, and potentially also catalyzes the reverse reaction.
[44]
Role of Ceramidases in Sphingolipid Metabolism and Human ...
Ceramidase is key in the degradation of ceramide into sphingosine and free fatty acids. In humans, five different ceramidases are known—acid ceramidase, neutral ...
[45]
Structural basis for the activation of acid ceramidase - Nature
Apr 24, 2018 · Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into sphingosine, the backbone of all sphingolipids, to regulate many cellular processes.
[46]
Elusive Roles of the Different Ceramidases in Human Health ...
ALKCDases are predominantly located in the Golgi complex and endoplasmic reticulum and play a role in cell differentiation [11]. ACER1 hydrolyses C20:0-C24:0 ...
[47]
Alkaline ceramidase 2 is essential for the homeostasis of plasma ...
Jan 22, 2018 · This is via the action of the acid, neutral, and alkaline ceramidase subtypes that are encoded by 5 distinct genes: ASAH1, ASAH2, ACER1, ACER2, ...
[48]
ASAH2 - Neutral ceramidase - Homo sapiens (Human) - UniProt
Plasma membrane ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at neutral pH.
[49]
regulators of cellular responses mediated by ceramide, sphingosine ...
Ceramidases catalyze hydrolysis of ceramides to generate sphingosine (SPH), which is phosphorylated to form sphingosine-1-phosphate (S1P).
[50]
Acid ceramidase controls apoptosis and increases autophagy in ...
May 27, 2021 · One such agent, doxorubicin, was shown to increase ceramide levels in melanoma cells. Ceramides contribute to the regulation of autophagy and ...
[51]
ASAH1-Related Disorders - GeneReviews® - NCBI Bookshelf
Mar 29, 2018 · ASAH1-related disorders comprise a spectrum that ranges from Farber disease (FD) to spinal muscular atrophy (SMA) with or without epilepsy.
[52]
Lipid and Lipoprotein Metabolism in Microglia: Alzheimer's Disease ...
Aug 5, 2025 · ... ceramidase (ASAH1) and alkaline ceramidase 3 (ACER3), suggesting that microglia are capable of de novo ceramide synthesis and conversation ...
[53]
Models of the Three-Component Bilayer of Stratum Corneum
In this layer the main lipid classes are ceramides, cholesterol (CHOL), and FFA. Previous studies revealed a coexistence of two cryst. lamellar phases with ...Missing: plasma | Show results with:plasma
[54]
Inimitable Impacts of Ceramides on Lipid Rafts Formed in Artificial ...
Jul 23, 2022 · One of the most remarkable findings of these studies is that ceramide induces the coalescence of membrane domains termed lipid rafts.
[55]
Review. Ceramide: from lateral segregation to mechanical stress
Ceramide is a sphingolipid present in eukaryotic cells that laterally segregates into solid domains in model lipid membranes. Imaging has provided a wealth ...
[56]
Whole picture of human stratum corneum ceramides, including the ...
Ceramides containing an LCB whose chain length was C16–26 were present in the human SC. Of these, C18 (28.6%) was the most abundant, followed by C20 (24.8%) and ...
[57]
Ceramides and Skin Health: New Insights - Wiley Online Library
Feb 6, 2025 · Studies done in vitro have demonstrated that at pH 5.5, SC lipids reorganise to create multilayers, whereas at pH 7.4, only monolayers were ...
[58]
Ceramide Selectively Displaces Cholesterol from Ordered Lipid ...
This would double the value for ceramide levels produced in the outer leaflet to 24 mol%. Several other studies have shown that SMase digestion also leads to ...<|control11|><|separator|>
[59]
The Effect of Ceramide Ratio on the Membrane Curvature of Mimetic ...
Jun 9, 2025 · Our findings reveal that increasing the CER content up to 25% significantly enhances membrane curvature, as demonstrated by changes in experimental ...
[60]
Ceramide‐rich platforms in transmembrane signaling - FEBS Press
Feb 20, 2010 · This review details the capability of ceramide to reorganize membranes based on its unique biophysical properties, linking its biological and ...Ceramide-Rich Platforms In... · 2 Ceramide: Biology And... · 3 Ceramide-Rich Platforms
[61]
Ceramide signaling in cancer and stem cells - PMC - PubMed Central
In addition to its immediate cell-signaling function, ceramide serves as a metabolic precursor for another important cell-signaling lipid, S1P. Ceramide is ...
[62]
Ceramide in Stress Response - PMC - PubMed Central - NIH
This chapter discusses the seminal and more recent discoveries in regards to the pathways responsible for the accumulation of ceramide during stress and the ...
[63]
Ceramide-Initiated Protein Phosphatase 2A Activation Contributes to ...
We show in endothelial cells that ceramide associates with the inhibitor 2 of PP2A (I2PP2A) in the cytosol, which disrupts the association of I2PP2A with PP2A ...
[64]
Ceramide Mediates Vascular Dysfunction in Diet-Induced Obesity by ...
We conclude that ceramide mediates obesity-related vascular dysfunction by a mechanism that involves PP2A-mediated disruption of the eNOS/Akt/Hsp90 signaling ...
[65]
CERAMIDE-RICH PLATFORMS IN TRANSMEMBRANE SIGNALING
Recent evidence suggests that ceramide regulates stress signaling via reorganization of the plasma membrane. The focus of this review will be to discuss the ...
[66]
Ceramides as Mediators of Oxidative Stress and Inflammation in ...
This review reports available evidence on ceramide structure and generation, and discusses their role in cardiometabolic disease.
[67]
The long and the short of ceramides - PMC - NIH
Jun 22, 2018 · For example, in cells derived from squamous cell carcinoma, C16-ceramide was reported to be anti-apoptotic and C18-ceramide pro-apoptotic (3), ...
[68]
C16 ceramide is crucial for triacylglycerol-induced apoptosis in ... - NIH
Mar 15, 2012 · Overexpression of ceramide synthases was sufficient to induce mitochondrial apoptosis in Wt macrophages. In accordance, inhibition of ceramide ...<|control11|><|separator|>
[69]
Many Ceramides - PMC - NIH
Ceramide (Cer) is synthesized de novo in the ER and then is transported either via ceramide transfer protein (CERT) to the Golgi, where it serves as a substrate ...
[70]
Novel Pathway of Ceramide Production in Mitochondria
Here we report that liver mitochondria exhibit ceramide formation from sphingosine and palmitoyl-CoA and from sphingosine and palmitate.
[71]
Ceramide signaling in immunity: a molecular perspective - PMC
Jul 1, 2025 · Ceramides are bioactive lipids that play a crucial role in cellular signaling and structural integrity (Nat Rev Mol Cell Biol 19:175-191, ...
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Mitochondrial Ceramide and the Induction of Apoptosis - PMC - NIH
Ceramide has been shown to form large protein permeable channels in planar phospholipid and mitochondrial outer membranes. Thus, ceramide channels are good ...
[73]
Anti-apoptotic Bcl-2 Family Proteins Disassemble Ceramide Channels
Ceramide-induced mitochondria-mediated apoptosis is inhibited by the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL (28, 35–37). However, a key question ...
[74]
Ceramide-induced integrated stress response overcomes Bcl-2 ...
Jun 30, 2022 · Ceramides induce ISR activation and sensitize cells to Bcl-2 inhibition. ... Ceramide channels: destabilization by Bcl-xL and role in apoptosis .
[75]
Cathepsin D links TNF-induced acid sphingomyelinase to Bid ...
Jan 23, 2004 · This study identifies CTSD as the missing link between TNF-activated ceramide production by A-SMase and the induction of apoptotic signalling ...
[76]
Ceramides and ceramide synthases in cancer: Focus on apoptosis ...
Ceramides with various fatty acyl chain lengths such as C2-, C8-, C16- and C24-ceramides are capable of perforating the mitochondrial outer membranes (Ho et al.
[77]
Traceless synthesis of ceramides in living cells reveals saturation ...
Jul 2, 2018 · We directly confirm the proapoptotic effects of C16:0 ceramide in vivo and observe that ceramide saturation plays a determinant role in ceramide-driven ...
[78]
Apoptotic Sphingolipid Ceramide in Cancer Therapy - PMC - NIH
Jan 13, 2011 · Ceramide acts as tumor-suppressor lipid because a variety of stress stimuli cause apoptosis by increasing intracellular ceramide to initiate apoptotic ...
[79]
Ceramide synthases 2, 5, and 6 confer distinct roles in radiation ...
IR-induced apoptosis was preceded by dose-dependent elevation in total cellular ceramide, with a maximal 2.34-fold increase 28 h after 15 Gy (Fig. 1B and ...
[80]
Roles for C16-ceramide and Sphingosine 1-Phosphate in ...
... C16-ceramide was significantly reduced, again implicating this specific ceramide in mediating apoptosis. In addition to changes in ceramide, overexpression ...
[81]
Ceramide-induced apoptosis in renal tubular cells: a role ... - PubMed
Mar 5, 2015 · Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis.
[82]
The chemistry, function and (patho)physiology of stratum corneum ...
Mar 24, 2017 · Thirteen classes of ceramides with over 300 and possibly up to 1000 distinct ceramide species have been identified suggesting an exquisitely ...
[83]
ω-O-Acylceramides but not ω-hydroxy ceramides are required for ...
Epidermal omega-O-acylceramides (ω-O-acylCers) are essential components of a competent skin barrier. These unusual sphingolipids with ultralong N-acyl ...
[84]
The Pathogenic and Therapeutic Implications of Ceramide ... - MDPI
In the skin, ceramides and other lipids play an essential role in forming a permeability barrier in the stratum corneum (SC), preventing excessive water loss ...
[85]
Lipids and the Permeability and Antimicrobial Barriers of the Skin - NIH
Free long-chain bases derived from ceramides in the stratum corneum serve as broader acting antimicrobial agents at the surface of the skin and its appendages.
[86]
Accelerated Barrier Repair in Human Skin Explants Induced with a ...
Sep 18, 2021 · PPAR-α activators induce keratinocyte differentiation and epidermal lipid synthesis, including ceramide production, thus accelerating the ...
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Clinical significance of the water retention and barrier function ...
Oct 15, 2021 · A decrease in the ceramide content of the stratum corneum is known to cause dry and barrier‐disrupted skin. In this literature review, ...
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Early-life protein-bound skin ceramides help predict the ...
Feb 11, 2025 · Early-life protein-bound skin ceramides help predict the development of atopic dermatitis. Equal senior authors.
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https://pubmed.ncbi.nlm.nih.gov/24106929/
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The Role of Ceramides in Insulin Resistance - PubMed
Aug 21, 2019 · The accumulation of sphingolipid ceramide in tissues of obese humans, rodents and Western-diet non-human primates is in line with diabetes, ...
[94]
Inhibition of ceramide de novo synthesis reduces liver ... - PubMed
Conclusions: Inhibition of ceramide de novo synthesis reduced hepatic lipid accumulation in rats with NAFLD, this led to amelioration of hepatic steatosis.
[95]
Regulation of insulin action by ceramide: dual mechanisms linking ...
Aug 27, 2004 · The sphingolipid ceramide negatively regulates insulin action by inhibiting Akt/protein kinase B (PKB), a serine/threonine kinase that is a central regulator ...
[96]
Ceramide generation is sufficient to account for the inhibition of the ...
Aug 20, 1999 · Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated ...
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Receptor-mediated activation of ceramidase activity initiates the ...
Dec 26, 2010 · We show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism.
[98]
The role of adipokines as regulators of skeletal muscle fatty acid ...
Thus, leptin and adiponectin resistance may be an initiating factor in the accumulation of intramuscular lipids, such as diacylglycerol and ceramide, and the ...
[99]
Obesity-induced CerS6-dependent C16:0 ceramide ... - PubMed
Oct 7, 2014 · Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with ...<|control11|><|separator|>
[100]
Central role of ceramide biosynthesis in body weight regulation ...
Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis, and improved glucose hemostasis ...
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Plasma 16:0 ceramide as a marker of cardiovascular risk estimated ...
May 4, 2024 · Plasma ceramides emerge as promising candidates, given their substantial influence on the pathogenesis of both T2DM and atherosclerosis.
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Ceramides-Emerging Biomarkers of Lipotoxicity in Obesity, Diabetes ...
Aug 23, 2024 · Recent studies suggest that Cer lipotoxicity has an important role in obesity, metabolic syndrome, type 2 diabetes, atherosclerosis, and cardiovascular ...
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Circulating ceramides as biomarkers of cardiovascular disease
Recent studies have highlighted circulating ceramides as novel biomarkers of coronary artery disease, type-2 diabetes and insulin resistance.
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The Carboxyl-terminal Domain of Atypical Protein Kinase Cζ Binds ...
May 22, 2009 · Ceramide interaction with the C20ζ binding domain is a potential mechanism by which ceramide and aPKC regulate the formation of junctional complexes in ...
[105]
Sphingolipid Metabolic Pathway: An Overview of Major Roles ...
The de novo biosynthesis of ceramide which occurs in ER is represented by the compartment C1.
[106]
Ceramide in the Molecular Mechanisms of Neuronal Cell Death. The ...
Cell-permeable short chain ceramide, C2-ceramide and C6-ceramide have been used in many studies to mimic ceramide-mediated cell death pathways. It was shown ...
[107]
Biochemistry of very-long-chain and long-chain ceramides in cystic ...
Part of the answer to these questions seems to lie in the structural role of ceramides as the fundamental building blocks of all eukaryotic cell membranes.
[108]
Alterations to Sphingomyelin Metabolism Affect Hemostasis and ...
Recent studies showed that SARS-CoV-2 infection activates ASMase, and the ASMase-induced membrane changes play a crucial role in SARS-CoV-2 entry into ...<|control11|><|separator|>
[109]
Overexpression of Akt (protein kinase B) confers protection against ...
Overexpression of PI3K (p110) and Akt protected cells against ceramide-induced apoptosis, suggesting that Ceramide action is upstream of Akt in these cells.
[110]
Ceramide activates heterotrimeric protein phosphatase 2A - PubMed
Jul 25, 1993 · Ceramide-activated protein phosphatase (CAPP) was found to share several properties with protein phosphatase 2A (PP2A) leading to the hypothesis ...
[111]
The structural requirements for ceramide activation of ... - PubMed
This study demonstrates strict structural requirements for interaction of ceramide with CAPP, and disclose ceramide as a very specific regulator of CAPP. The ...
[112]
Ceramide Induces Mitochondrial Activation and Apoptosis via a Bax ...
... ceramide-induced death signalling has not yet been studied in detail. In the present work, we show by measurement of mitochondrial permeability transition ...
[113]
Ceramide induces release of pro-apoptotic proteins from ... - PubMed
... ceramide causes cytochrome c release through a Ca2+ -dependent and CsA sensitive mitochondrial permeability transition (MPT) mechanism. The latter effect ...
[114]
Induction of ER stress-mediated apoptosis by ceramide ... - PubMed
Nov 25, 2014 · Moreover, the ceramide synthase inhibitor FB1 abolished ceramide-induced ER stress ... Ceramide; ER calcium; ER stress; Unfolded protein response.
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Linking the unfolded protein response to bioactive lipid metabolism ...
Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are ...
[116]
Ceramide glycosylation catalyzed by glucosylceramide synthase ...
Glucosylceramide synthase (GCS), converting ceramide to glucosylceramide, catalyzes the first reaction of ceramide glycosylation in sphingolipid metabolism.
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Ceramide-domain formation and collapse in lipid rafts - PubMed
Ceramide-domain formation and collapse in lipid rafts: membrane reorganization by an apoptotic lipid. Biophys J. 2007 Jan 15;92(2):502-16. doi: 10.1529 ...
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Neuroprotective effect of neuron-specific deletion of the C16 ...
Ceramide C16 is a sphingolipid detected at high levels in several neurodegenerative disorders, including multiple sclerosis (MS).Missing: ceramidase | Show results with:ceramidase
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Glia | Neurobiology Journal | Wiley Online Library
Nov 3, 2024 · At a cellular level, neurons lacking both CerS6 and CerS5 are protected from the mitochondrial dysfunction arising from exposure to oxidative ...
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Ceramide sensing by human SPT-ORMDL complex for establishing ...
Jun 13, 2023 · Our work elucidates the molecular basis of ceramide sensing by the SPT-ORMDL complex for establishing sphingolipid homeostasis.
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International Journal of Molecular Medicine - Spandidos Publications
Dec 22, 2016 · CerS, ceramide synthases. Activation of the p38 MAPK/NF-κB pathway plays a critical role in hepatic inflammatory cytokine secretion. MAPK ...Results · Palmitate And Cers6 Have... · Lps Increases Tnf-α...<|control11|><|separator|>
[122]
Regulation of de novo sphingolipid biosynthesis by the ORMDL ...
We find that the ORMDL proteins are also negative regulators of SPT that transmit cellular levels of sphingolipids to SPT. The three isoforms have redundant ...Missing: endogenous NF- κB CerS SphK autophagy insulin UV hypoxia ASMase
[123]
SphK1 and SphK2, Sphingosine Kinase Isoenzymes with Opposing ...
In contrast, cytosolic S1P formed by SphK1 inhibits ceramide biosynthesis possibly as a cellular sensing mechanism to regulate levels of ceramide (Fig. 12).
[124]
Autophagy regulates sphingolipid levels in the liver[S]
The results reveal autophagy as a process that limits excessive ceramide levels and that is induced by excessive elevation of de novo sphingolipid synthesis in ...
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Ultraviolet B radiation induces activation of neutral and acidic ...
Aug 7, 2025 · The aim of this study is to investigate whether activation of SMases and generation of ceramide can be induced by UVB radiation in normal human ...
[126]
Ceramide Generated by Sphingomyelin Hydrolysis and the Salvage ...
These results suggest that elevated aSMase activity during hypoxia is important for ceramide up-regulation and for subsequent Bax translocation to mitochondria.Missing: trafficking | Show results with:trafficking
[127]
Regulated Secretion of Acid Sphingomyelinase - ScienceDirect
In response to TNF-α and IL-1β, S-SMase is up-regulated in a time- and dose-dependent manner, as is the formation of specific ceramide species. Moreover, we ...
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Functional roles of sphingolipids in immunity and their implication in ...
Jun 1, 2023 · In this review, we analyze sphingolipid-related enzymes and reported human diseases to understand the important roles of sphingolipid metabolism.
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[PDF] Ceramide signaling in the gut - ScienceDirect.com
Previous studies have shown that. TNF-α, IL-1, and other cytokines increase ceramides levels in different tissues and cell lines by activating SMase [21] ...Missing: inducers | Show results with:inducers
[130]
Daunorubicin-induced apoptosis: triggering of ceramide generation ...
... induced by chemotherapeutic agents. Here we show that in the leukemic cell lines U937 and HL-60, daunorubicin, at concentrations which trigger apoptosis ...
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Fenretinide stimulates redox-sensitive ceramide production in breast ...
Oct 26, 2004 · The nature and relevance of ceramide production and signalling, and its relationship to redox status during 4HPR action in human breast cancer ...Missing: ASMase | Show results with:ASMase
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H2O2 acts on cellular membranes to generate ceramide signaling ...
Nov 1, 1998 · It has also been recently reported that oxidative stress may activate growth-stimulatory responses similar to those induced by hormones and ...Annexin V Binding To... · Lipid Studies · Ho Induces Apoptosis In...<|separator|>
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Ceramide-rich platforms in transmembrane signaling - ScienceDirect
May 3, 2010 · The focus of this review will be to discuss the mechanism by which acid sphingomyelinase (ASMase)-generated ceramide initiates transmembrane ...
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Targeting sphingolipid metabolism: inhibition of neutral ...
Aug 14, 2025 · Interestingly, our study revealed that aSMase supports the replication of SARS-CoV-2 but has no major role in MERS-CoV or HCoV-229E replication.
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Role of Ceramide in SARS-CoV-2 Spike Protein-amplified Acute ...
We posit that increased ceramides are the result of the stress-induced activation of acid sphingomyelinase (ASM) on endothelial cells. ASM can be activated by ...
[136]
The yins and yangs of ceramide | Cell Research - Nature
Mar 1, 1999 · Ceramide, a mediator of interleukin 1, tumor necrosis factor alpha, as well as Fas receptor signaling, induces apoptosis of rheumatoid ...Missing: inducers | Show results with:inducers
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Induction of ER stress-mediated apoptosis by ceramide via ...
Moreover, ceramide induced the ER stress response in a time- and dose-dependent manner, in support of the statement that the ER stress is increased as the ...
[138]
The Pathogenic and Therapeutic Implications of Ceramide ...
In the skin, ceramides and other lipids play an essential role in forming a permeability barrier in the stratum corneum (SC), preventing excessive water loss ...
[139]
Intercellular Skin Barrier Lipid Composition and Organization in ...
Netherton syndrome (NTS) is a rare genetic skin disease caused by mutations in the serine protease inhibitor Kazal-type 5 gene, which encodes the ...
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Key regulators and biomarkers of skin barrier function in atopic ...
Apr 7, 2025 · Stratum corneum (SC) pH and ceramides are key regulators of skin barrier function. Elevated SC pH disrupts the skin barrier and exacerbates inflammation.<|control11|><|separator|>
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Lesional Psoriasis is Associated With Alterations in the Stratum ...
Oct 9, 2024 · The reduction in average CCL in lesional psoriatic skin is in line with previous work where an increase in the level of short-chain ceramides ...Missing: elevated | Show results with:elevated
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Increased Levels of Short-Chain Ceramides Modify the Lipid ...
Jul 28, 2021 · High levels of short-chain CERs are observed in various inflammatory skin diseases and have been correlated with barrier dysfunction.<|control11|><|separator|>
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Guselkumab treatment normalizes the stratum corneum ceramide ...
Jul 9, 2024 · Increase in short-chain ceramides ... Changes in fatty acid lengths of ceramides toward shorter chain dominance in human psoriasis skin.
[144]
Skin barrier lipid enzyme activity in Netherton patients is associated ...
Individuals with Netherton syndrome (NTS) have increased serine protease activity, which strongly impacts the barrier function of the skin epidermis and leads ...
[145]
Aging-associated alterations in epidermal function and their clinical ...
Mar 27, 2020 · Ceramide 1 and ceramide 3 act synergistically on skin hydration and the transepidermal water loss of sodium lauryl sulfate-irritated skin.
[146]
LC/MS analysis of stratum corneum lipids: ceramide profiling and ...
In this paper, a novel quick and robust LC/MS method is presented that allows the separation and analysis of all known human SC CER subclasses using only ...
[147]
52272 Ceramide profiling of atopic dermatitis and effects of ... - JAAD
Ceramides were extracted from the tapes and profiled using shotgun mass spectrometry. Results: Total ceramide levels were lower at lesional sites than at non- ...
[148]
Correlations between Skin Condition Parameters and Ceramide ...
Jul 29, 2024 · In the present study, we measured six skin condition parameters (capacitance, transepidermal water loss, scaliness, roughness, multilayer exfoliation, and ...
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Insulin resistance induced by de novo pathway–generated C16 ...
Feb 20, 2022 · The present study indicates that C16-ceramide plays a pivotal role in inducing insulin resistance. Overexpression of SPT1 in the obese-diabetic ...
[150]
Ceramide Content in Liver Increases Along with Insulin Resistance ...
Interestingly, glucose (at 0′ and at 120′ in OGTT) and HbA1c positively correlated with the ceramide species that most increased in T2D patients (C16:0-Cer, C18 ...
[151]
Plasma Ceramides Are Elevated in Obese Subjects With Type 2 ...
Feb 1, 2009 · Type 2 diabetic subjects had higher (P < 0.05) concentrations of C18:0, C20:0, C24:1, and total ceramide. Insulin sensitivity was inversely ...Missing: HbA1c | Show results with:HbA1c
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Plasma Membrane Subdomain Compartmentalization Contributes to ...
Dec 3, 2009 · Ceramide is now recognized as a negative regulator of insulin signaling by impairing protein kinase B (PKB)/Akt activation.
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Ceramide Metabolism in Cardiovascular Disease: A Network With ...
Aug 25, 2022 · The de novo synthesis of ceramides is initiated by the reaction of palmitoyl-CoA and serine to produce 3-keto-sphinganine, which is a precursor ...Ceramide Metabolism · De Novo Synthesis Pathway · Ceramide Synthases
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Science Saturday: Plasma ceramides - A promising new diagnostic ...
May 19, 2018 · Ceramides increase LDL infiltration and promote LDL aggregation (A), are upregulated in response to inflammatory cytokines (B), are enriched in atherosclerotic ...<|separator|>
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Ceramide: A Common Pathway for Atherosclerosis? - PMC
Ceramide, the backbone of sphingolipids, is the key component which affects atherosclerotic changes through its important second-messenger role.
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Ceramide Risk Score in the Evaluation of Metabolic Syndrome - NIH
Aug 5, 2023 · ... Plasma ceramides independently predict coronary artery disease and major adverse cardiovascular events. J. Clin. Lipidol. 2016;10:656–657 ...
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Sphingolipids and metabolic disease: Will the real killer please ...
In particular, the ratio of Cer 16:0/24:0 and Cer 24:1/24:0 is associated with an increased fatal risk in patients with cardiovascular disease.
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Adipocyte Ceramides—The Nexus of Inflammation and Metabolic ...
Ceramide accumulation elicits deleterious effects on adipose tissue function by activating Nlrp3 inflammasome that induces inflammation, inhibition of Akt via ...
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Acid sphingomyelinase as a pathological and therapeutic target in ...
Feb 9, 2024 · Acid sphingomyelinase (ASM), a significant sphingolipid-metabolizing enzyme, plays a specific role in sphingomyelin hydrolysis into ceramide and ...
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Inhibition of Ceramide Synthesis Reduces α-Synuclein ... - NIH
Jun 16, 2021 · Inhibition of ceramide synthesis reduces α-synuclein proteinopathy in a cellular model of Parkinson's disease.
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The physiological and pathological effects of sphingolipid ...
Jul 31, 2025 · However, clinical studies have found significantly elevated aSMase activity in the blood cells or plasma of patients with depression [206].
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Exogenous Ceramide Treatment Induce Death and Cytotoxicity in ...
Glioblastoma cells undergo apoptosis when exposed to C6 ceramide, which makes it a potential chemotherapeutic agent for the treatment of this aggressive ...
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Human CPTP promotes growth and metastasis via sphingolipid ...
Jul 27, 2022 · Human CPTP promotes growth and metastasis via sphingolipid metabolite ceramide and PI4KA/AKT signaling in pancreatic cancer cells ... autophagy ...
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The Efficacy of Moisturisers Containing Ceramide Compared with ...
Moisturisers containing ceramide are more effective at improving AD severity—as shown by SCORAD changes—but are not better at improving TEWL when compared to ...
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Considering Phytosphingosine-Based Ceramide Formulations for ...
Mar 13, 2024 · There are two primary packing conformations within the lipid lamellae: (1) orthorhombic packing (ORTHO) and (2) hexagonal packing (HEX). The ...Missing: 0 | Show results with:0
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Efficacy of Topical Application of a Skin Moisturizer Containing ...
Mar 18, 2024 · Treatments to increase ceramide levels are effective for AD care. Synthetic pseudo-ceramide (cetyl PG hydroxyethyl palmitamide (SLE66)), which ...
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Nanoliposome C6-Ceramide Increases the Anti-tumor Immune ... - NIH
Ceramide, a sphingolipid metabolite, affects T-cell signaling, induces apoptosis of cancer cells, and slows tumor growth in mice.Missing: nanoparticles | Show results with:nanoparticles
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Ceramide-Graphene Oxide Nanoparticles Enhance Cytotoxicity and ...
Feb 7, 2019 · Previous work has shown that exogenous ceramide can play a key role in inducing the apoptotic death of cancer cells, however, the poor water- ...
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Synergistic Combination Therapy with Nanoliposomal C6-Ceramide ...
Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells. J Pharmacol Exp Ther. 2003;307:468–475. doi: 10.1124/jpet ...
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C24 Ceramide Lipid Nanoparticles for Skin Wound Healing - PMC
Feb 12, 2025 · Background/Objectives: C24 ceramide plays a crucial role in skin regeneration and wound healing; however, its hydrophobic nature limits its ...
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The effect of a hydrocolloid dressing containing ceramide-2 on split ...
Topical ceramides therapy has currently been used to improve skin barrier function. However, little is known about the effect of topical ceramides on wound ...
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The ceramide [NP]/[NS] ratio in the stratum corneum is a potential ...
Aug 31, 2020 · The Cer [NP]/[NS] ratio in the SC is a potential marker for skin properties and epidermal differentiation in barrier-disrupted skin as well as in healthy skin.Missing: creams | Show results with:creams
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Improving the quality of life of patients with inflammatory skin diseases
A ceramide-containing regimen reduced the symptoms commonly associated with AD, psoriasis, and xerosis and improves patients' QoL.Missing: Cer- | Show results with:Cer-<|control11|><|separator|>
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Occurrence of Free Ceramides in Bacteroides fragilis - J-Stage
The occurrence of free ceramides at high concentrations was demonstrated in the chloroform methanol extractable lipids of Bacteroides fragilis NCTC 9343.
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Occurrence of ceramides in the Acidobacterium Solibacter usitatus
Jul 9, 2024 · The occurrence of ceramides has not been previously reported within the Acidobacteria, a bacterial phylum that is an abundant and diverse ...
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Convergent evolution of bacterial ceramide synthesis - Nature
Dec 30, 2021 · Here we used genomic and biochemical approaches to identify six proteins comprising the complete pathway for bacterial ceramide synthesis.
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Five structural genes required for ceramide synthesis in Caulobacter ...
At least five structural genes are required for dihydroceramide biosynthesis in C. crescentus and sphingolipid biosynthesis is needed for survival of this ...
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Membrane sphingolipids as essential molecular signals for ... - PNAS
Sep 20, 2010 · We propose that to persist in the intestine Bacteroides take advantage of their unusual bacterial sphingolipids to mediate signaling pathways.
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Requirement of ceramide for adhesion of <i>Helicobacter pylori</i ...
These bacteria were found to adhere to sulfatide, GM3, GalCer and LacCer, but not to ceramide, sphingomyelin, or polyacrylamides conjugated with. L-galactose, ...<|separator|>
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Abstract 4141726: Ceramides produced by gut bacteria Bacteroides ...
Nov 11, 2024 · Introduction: Specific ceramides play a crucial role in cellular senescence by upregulating the SASP in the vasculature, ...
[182]
Ceramide phosphoethanolamine, an enigmatic cellular membrane ...
Ceramide phosphoethanolamine (CPE) is the major sphingolipid in invertebrates and in some bacterial species. It has been also detected in mammalian cells.
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https://www.nature.com/articles/s41589-021-00948-7
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Sphingolipid biosynthesis in man and microbes - RSC Publishing
Jun 4, 2018 · This review covers the structural, mechanistic and regulatory features of sphingolipid biosynthetic and metabolic enzymes.2 Serine... · 5 Sphingosine 1-Phosphate... · 9 References
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Role and interaction of bacterial sphingolipids in human health
Oct 22, 2023 · Research studies have indicated the presence of approximately 10% undegraded sphingomyelin and 30–90% ceramide in mouse feces (Norris et al., ...
[186]
Bacteroides-derived sphingolipids are critical for maintaining ...
A lack of Bacteroides-derived sphingolipids resulted in intestinal inflammation and altered host ceramide pools in mice. Using lipidomic analysis, we described ...