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Sphingomyelin

Sphingomyelin is a sphingophospholipid composed of a ceramide backbone—a sphingosine base linked via an amide bond to a fatty acid chain—with a phosphorylcholine head group attached to the C1 position of the sphingosine, making it structurally similar to phosphatidylcholine but with a sphingoid base instead of a glycerol backbone.^[1] It is one of the most abundant sphingolipids in mammalian cells, serving as a major structural component of plasma membranes, where it contributes to membrane fluidity, stability, and the formation of lipid rafts that facilitate protein sorting, signaling, and vesicular trafficking.^[2] Particularly enriched in the myelin sheath surrounding nerve fibers, sphingomyelin plays a critical role in neuronal insulation and rapid signal conduction.^[3] Beyond its structural functions, sphingomyelin acts as a precursor in the sphingolipid metabolic pathway, where it can be hydrolyzed by sphingomyelinases to generate ceramide and phosphorylcholine, molecules involved in cell signaling, apoptosis, inflammation, and stress responses.^[4] This metabolism is tightly regulated in organelles like the Golgi apparatus and plasma membrane, with sphingomyelin synthases catalyzing its synthesis from ceramide and phosphatidylcholine.^[2] Dietary sphingomyelin, sourced from foods such as milk, eggs, and meat, is absorbed in the intestine and contributes to host sphingolipid pools, supporting gut health, cholesterol homeostasis, and potentially neurodevelopment.^[5] Dysregulation of sphingomyelin metabolism is implicated in various diseases; for instance, deficiencies in acid sphingomyelinase lead to sphingomyelin accumulation in lysosomes, causing Niemann-Pick disease types A and B, which manifest as progressive neurodegeneration, hepatosplenomegaly, and lung dysfunction.^[6] In other contexts, altered sphingomyelin levels are associated with cardiovascular disorders, due to its presence in plasma lipoproteins, and with viral infections, such as hepatitis C, where it supports replication organelle formation.^[7]^[2] Overall, sphingomyelin's dual roles in membrane architecture and bioactive lipid signaling underscore its essentiality in cellular physiology and disease pathology.

Chemical Structure and Properties

Molecular Composition

Sphingomyelin is classified as a sphingophospholipid, distinguished by its ceramide backbone, which consists of a sphingoid base—typically sphingosine, an 18-carbon amino alcohol with a trans double bond between carbons 4 and 5 (d18:1)—covalently linked to a fatty acid through an amide bond at the amino group of the sphingoid base.^[8]^[9] This ceramide structure forms the hydrophobic core of the molecule, providing rigidity due to the linear sphingoid base and the amide linkage, which contrasts with the more flexible ester bonds in other lipids.^[8] The hydrophilic head group of sphingomyelin is phosphocholine, attached to the primary hydroxyl group at the C1 position of the ceramide via a phosphodiester bond.^[8]^[9] This attachment creates an amphipathic molecule with a polar head and nonpolar tails, enabling its integration into lipid bilayers. The fatty acid component exhibits significant variation, commonly ranging from 14 to 26 carbons in length, with C16:0 (palmitic acid) and C18:0 (stearic acid) being prevalent, though monounsaturated chains like C24:1 are also common, particularly in neural tissues.^[8]^[10] These variations influence the molecule's packing properties without altering the core architecture.^[10] The general structural formula of sphingomyelin is represented as N-acyl-sphingosine-1-phosphocholine, where the acyl group denotes the fatty acid.^[8] A specific example is N-stearoyl-sphingosine-1-phosphocholine (SM d18:1/18:0), which features an 18-carbon sphingosine base and an 18-carbon saturated fatty acid, commonly found in mammalian cell membranes.^[8]^[9] Another representative species is N-palmitoyl-sphingosine-1-phosphocholine (SM d18:1/16:0), highlighting the diversity in acyl chain length.^[8] Unlike glycerophospholipids, which rely on a three-carbon glycerol backbone esterified to two fatty acids and a phosphate-linked head group, sphingomyelin lacks glycerol and instead uses the sphingoid base for its single fatty acid attachment, resulting in a more elongated and rigid structure.^[8] In comparison to other sphingolipids, such as glycosphingolipids, sphingomyelin uniquely incorporates the phosphocholine moiety rather than a carbohydrate chain, conferring distinct biochemical properties.^[8]^[9]

Physical and Chemical Properties

Sphingomyelin (SM) is an amphipathic molecule characterized by a hydrophilic phosphocholine headgroup attached to a hydrophobic ceramide moiety, consisting of a sphingosine backbone linked via an amide bond to a fatty acyl chain; this structural duality enables SM to self-assemble into lipid bilayers in aqueous environments.^[11]^[12] The phase behavior of SM is marked by a high main chain-melting transition temperature (T_m), typically ranging from 37°C to 48°C for common saturated species such as N-palmitoyl-SM (T_m ≈ 41°C) and N-stearoyl-SM (T_m ≈ 45°C), attributed to strong van der Waals interactions among the saturated acyl chains and intermolecular hydrogen bonding involving the amide group and headgroup.^[11]^[13] In contrast to phosphatidylcholines (PCs), which often exhibit lower T_m values and transition to fluid phases near physiological temperatures, SM tends to maintain ordered gel phases even at 37°C, resulting in more compact and rigid bilayers due to its enhanced packing efficiency and reduced chain mobility.^[14]^[12] SM demonstrates low solubility in water, with its polar region exhibiting limited hydration compared to PCs (fewer water molecules associating with the headgroup due to intramolecular hydrogen bonding in SM), which contributes to its stability in membrane contexts but necessitates organic solvents like chloroform-methanol mixtures (2:1 v/v) for extraction and solubilization.^[14]^[12] Chemically, SM exhibits greater resistance to enzymatic and chemical hydrolysis than glycerophospholipids, owing to the robust amide linkage in its ceramide tail versus the more labile ester bonds in PCs, enhancing its persistence in biological membranes.^[12] A notable interaction property of SM is its strong affinity for cholesterol, facilitated by hydrogen bonding between the sterol's hydroxyl group and SM's amide or phosphate moieties, which promotes the formation of tightly packed, liquid-ordered domains distinct from the liquid-disordered phases observed in PC-cholesterol mixtures.^[11]^[13] This association is particularly pronounced in SM species with saturated acyl chains of 16-18 carbons, underscoring how chain length subtly modulates these biophysical traits.^[14]

Biosynthesis and Metabolism

Biosynthetic Pathways

Sphingomyelin biosynthesis primarily occurs through the de novo pathway, which begins in the endoplasmic reticulum (ER) with the condensation of L-serine and palmitoyl-CoA to form 3-ketodihydrosphingosine, catalyzed by serine palmitoyltransferase (SPT).^[15] This rate-limiting step involves the core subunits SPTLC1 and SPTLC2, along with accessory subunits like SPTLC3 or small subunits (ssSPTs) that modulate activity, while ORMDL proteins act as inhibitors to regulate flux through the pathway.^[15] The intermediate 3-ketodihydrosphingosine is then reduced to sphinganine by 3-ketodihydrosphingosine reductase (KDSR), using NADPH as a cofactor. Subsequent acylation of sphinganine with a fatty acyl-CoA, facilitated by one of six ceramide synthase isoforms (CerS1-6), yields dihydroceramide; these enzymes exhibit substrate specificity, with CerS5 and CerS6 preferring shorter-chain fatty acids like palmitoyl-CoA. Dihydroceramide is desaturated by dihydroceramide desaturase (DEGS1 or DEGS2) to produce ceramide, the central precursor for sphingomyelin, completing the ER-localized de novo ceramide synthesis.^[15] Ceramide is transported from the ER to the Golgi apparatus via the CERT protein, where sphingomyelin synthase 1 (SMS1), localized in the trans-Golgi network, transfers a phosphocholine headgroup from phosphatidylcholine to ceramide, generating sphingomyelin and diacylglycerol.^[16] A second isoform, SMS2, performs the same reaction but is primarily localized to the plasma membrane, contributing to sphingomyelin production at the cell surface. An alternative salvage pathway recycles sphingosine, derived from the lysosomal degradation of complex sphingolipids, back into ceramide through re-acylation by CerS enzymes in the ER, bypassing the initial SPT step and allowing reutilization of sphingoid bases.^[15] This pathway supports sphingomyelin homeostasis under conditions of high sphingolipid turnover. Overall, de novo ceramide production predominates in the ER, while final sphingomyelin assembly occurs mainly in the Golgi, with both processes influenced by nutrient availability, such as fatty acids that modulate SPT activity indirectly through ORMDL regulation.^[16]

Catabolic Processes

Sphingomyelin catabolism primarily occurs through enzymatic hydrolysis mediated by sphingomyelinases (SMases), which cleave the phosphocholine head group from the sphingomyelin backbone, yielding ceramide and phosphocholine as primary products.^[17] These enzymes are classified based on their optimal pH and subcellular localization, enabling regulated breakdown in specific cellular compartments.^[17] The resulting ceramide serves as a central bioactive lipid that can be further metabolized, influencing cellular signaling and homeostasis.^[18] Acid sphingomyelinase (aSMase), encoded by the SMPD1 gene, operates at acidic pH and exists in two forms: lysosomal aSMase (L-aSMase) within endolysosomal compartments and secreted aSMase (S-aSMase) in extracellular spaces.^[17] Neutral sphingomyelinase (nSMase), particularly nSMase2 encoded by SMPD2, functions at neutral pH and is localized to the plasma membrane and Golgi apparatus, often within lipid rafts.^[17] Alkaline sphingomyelinase (alk-SMase), encoded by ENPP7, is active at alkaline pH and predominantly found in the intestinal mucosa and liver, where it is bile salt-dependent and crucial for dietary sphingomyelin digestion.^[17] Ceramide produced by these SMases undergoes further catabolism by ceramidases, which hydrolyze it into sphingosine and free fatty acids.^[17] Sphingosine is then phosphorylated by sphingosine kinases (SphK1 or SphK2) to form sphingosine-1-phosphate (S1P), a potent signaling molecule involved in cell migration, survival, and vascular permeability.^[17] This sequential degradation pathway links sphingomyelin breakdown to broader sphingolipid signaling networks.^[18] SMase activity is tightly regulated by external stimuli, including tumor necrosis factor-α (TNF-α) and oxidative stress (e.g., hydrogen peroxide), which activate both acid and neutral isoforms to rapidly generate ceramide.^[17] Compartmentalization ensures localized effects, as seen in lysosomal accumulation of sphingomyelin due to aSMase deficiency in conditions like Niemann-Pick disease, highlighting the enzyme's role in intracellular trafficking and storage.^[17] Sphingomyelin turnover is dynamic, occurring rapidly in response to signals with half-lives varying from hours to days across cell types, such as rapid readjustment in keratinocytes (half-maximal within minutes) versus slower pools in neural tissues (up to 14-69 days).^[19]^[20]

Distribution and Localization

Cellular and Subcellular Locations

Sphingomyelin is predominantly enriched in the outer leaflet of the plasma membrane in mammalian cells, where it constitutes approximately 10-20% of total phospholipids, contributing to membrane asymmetry and stability. This asymmetric distribution is maintained by ATP-dependent transporters such as ABC transporters, ensuring sphingomyelin's localization primarily in the exoplasmic leaflet while minimizing its presence in the cytoplasmic leaflet.^[21] Within the cell, sphingomyelin is synthesized in the Golgi apparatus, where sphingomyelin synthase enzymes transfer phosphocholine from phosphatidylcholine to ceramide. It is also present in endosomes and lysosomes, serving as sites for its degradation by sphingomyelinases into ceramide and phosphocholine.^[22]^[23] In contrast, sphingomyelin levels are low in the endoplasmic reticulum and mitochondria, reflecting limited roles in these organelles beyond precursor synthesis.^[16] In specialized structures like the myelin sheath of neurons, sphingomyelin is notably abundant, accounting for approximately 10% of brain lipids and higher in myelin, which supports compact multilayer formation essential for nerve insulation.^[24] Its subcellular dynamics can be monitored using fluorescent analogs, such as BODIPY-labeled sphingomyelin, which reveal translocation events during apoptosis—where sphingomyelin hydrolyzes and redistributes to inner leaflets or mitochondria—and signaling processes involving membrane raft reorganization.

Tissue and Organ Distribution

Sphingomyelin exhibits a heterogeneous distribution across mammalian tissues and organs, with notably high concentrations in the nervous system. It is predominant in the myelin sheath formed by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system, where it constitutes approximately 25% of total myelin lipids, playing a critical role in electrical insulation of axons.^[25] In the lungs, sphingomyelin accounts for about 20% of total phospholipids in lung tissue, contributing to membrane functions.^[26] Similarly, in the liver, hepatocytes incorporate sphingomyelin into lipoproteins for assembly and secretion, accounting for roughly 12% of phospholipids.^[26] Moderate levels of sphingomyelin are observed in the spleen, kidney, and intestine, typically ranging from 10% to 17% of total phospholipids, with the kidney showing higher enrichment at around 17%. In contrast, concentrations are lower in skeletal muscle (approximately 7%) and adipose tissue, where it represents less than 10% of phospholipids, reflecting differences in membrane demands and lipid composition across these sites.^[26]^[27] Developmentally, sphingomyelin levels in the brain rise markedly during myelination, increasing from about 2% of total lipids at birth to 15% by age 3 years and stabilizing at peak levels in adulthood, underscoring its association with neural maturation. Across species, sphingomyelin is more abundant in mammals than in invertebrates, particularly in neural tissues, where it supports advanced myelination absent in lower organisms. Dietary sphingomyelin intake also modulates intestinal levels by influencing absorption and local lipid dynamics.^[28]^[29]

Physiological Roles

Structural Role in Membranes

Sphingomyelin (SM), with its long, saturated acyl chains, contributes to the structural integrity of cellular membranes by promoting ordered lipid packing, which reduces membrane fluidity and permeability. This ordered arrangement arises from the high melting temperature of SM compared to other phospholipids, allowing it to form tightly packed domains that maintain membrane thickness and barrier function.^[30] In model bilayers, SM incorporation decreases the area per lipid to approximately 0.43–0.48 nm² and enhances acyl chain order, thereby limiting passive diffusion of ions and molecules across the membrane.^[30] The asymmetric distribution of SM, predominantly in the outer leaflet of the plasma membrane alongside phosphatidylcholine, is crucial for maintaining overall bilayer architecture and function. This enrichment in the exoplasmic leaflet, where SM constitutes a significant portion of lipids, helps establish transbilayer asymmetry that supports membrane potential through differences in leaflet dipole moments. The zwitterionic headgroup of SM contributes to a positive dipole potential (around 300–400 mV) in the outer leaflet, contrasting with the inner leaflet's anionic lipids and influencing electrostatic interactions that stabilize protein orientation and activity.^[31]^[32] Such asymmetry ensures proper topological insertion and function of transmembrane proteins, preventing disruptions that could compromise cellular homeostasis.^[32] SM interacts strongly with cholesterol via hydrogen bonding and van der Waals forces, forming stoichiometric complexes that further rigidify the membrane and enhance its barrier properties. These interactions increase lipid order and reduce lateral mobility, essential for selective permeability and overall membrane stability. In biological contexts, this complexation helps regulate cholesterol distribution and supports the membrane's role as a selective barrier.00188-0) In myelin sheaths, high SM content, often alongside galactosylceramide, enables the formation of compact, multilayered structures critical for rapid nerve conduction. SM's presence in peripheral nervous system myelin promotes tight apposition of lipid bilayers, increasing acyl chain order and impermeability to water and ions, which insulates axons effectively. This composition enhances the mechanical resilience of myelin, providing tensile strength against physical stress during neural activity.^[33] Overall, membrane lipid asymmetry, including SM's outer leaflet localization, bolsters tensile strength and resistance to mechanical deformation, as demonstrated in erythrocytes where symmetric scrambling reduces stability by twofold under shear stress.^[34]

Signaling and Transduction Functions

Sphingomyelin serves as a precursor in signaling pathways through its hydrolysis by sphingomyelinases (SMases), generating ceramide that acts as a bioactive lipid mediator. Acid sphingomyelinase (ASMase), in particular, hydrolyzes sphingomyelin to produce ceramide, which recruits and activates protein kinase C zeta (PKCζ) within lipid microdomains of the plasma membrane.95017-9/fulltext) This activation leads to the inhibition of Akt (protein kinase B) by promoting its dephosphorylation via protein phosphatase 2A, thereby modulating cellular responses to growth factors such as insulin-like growth factor I (IGF-I).^[35] Consequently, this pathway attenuates downstream signaling through the PI3K/Akt axis, influencing cell proliferation and survival in response to mitogenic stimuli.87612-1/fulltext) Further downstream in sphingomyelin metabolism, ceramide is converted to sphingosine, which is then phosphorylated by sphingosine kinases to yield sphingosine-1-phosphate (S1P). S1P acts as an extracellular signaling molecule that binds to G-protein-coupled receptors (GPCRs), notably S1PR1, to promote endothelial cell migration and vascular maturation during angiogenesis. This receptor-mediated signaling enhances cytoskeletal dynamics and chemotaxis, contributing to vessel stabilization and barrier function in developing vasculature.^[36] In the plasma membrane, sphingomyelin facilitates the clustering of transmembrane receptors, thereby enhancing signal transduction efficiency. For instance, sphingomyelin-enriched domains support the aggregation of epidermal growth factor receptor (EGFR), enabling its autophosphorylation and activation upon ligand binding, which propagates mitogenic signals.^[37] Similarly, sphingomyelin contributes to integrin clustering, promoting focal adhesion formation and mechanotransduction that integrates extracellular matrix cues with intracellular pathways like FAK/Src signaling.^[38] Within the nucleus, sphingomyelin localizes to the nuclear envelope and forms cholesterol-rich microdomains that regulate transcriptional and post-transcriptional processes. Recent investigations have shown that these nuclear sphingomyelin microdomains protect double-stranded RNA from exonuclease degradation, thereby influencing RNA processing and stability essential for gene expression.^[39] Additionally, sphingomyelin in these domains interacts with chromatin-modifying factors to modulate histone acetylation and transcription factor recruitment, fine-tuning gene transcription in response to cellular cues.^[39] Sphingomyelin engages in cross-talk with other lipid signaling molecules, particularly impacting the PI3K/Akt pathway during inflammatory responses. Ceramide derived from sphingomyelin hydrolysis antagonizes PI3K activation by inhibiting Akt phosphorylation, which dampens pro-inflammatory cytokine production in immune cells such as macrophages.^[40] This interaction with phosphoinositides like PIP3 alters membrane recruitment of signaling effectors, thereby balancing inflammatory signaling and preventing excessive immune activation.^[41]

Involvement in Programmed Cell Death

Sphingomyelinases (SMases) are activated during apoptosis, leading to the hydrolysis of sphingomyelin into ceramide, a key lipid mediator that promotes cell death signaling. Acid sphingomyelinase (ASMase), in particular, translocates to the plasma membrane or lysosomes upon apoptotic stimuli, generating ceramide that facilitates downstream events such as mitochondrial outer membrane permeabilization (MOMP).^[42]^[43] Ceramide generated from sphingomyelin hydrolysis induces the release of cytochrome c from mitochondria, which activates the apoptosome and initiates caspase-3 and -9 activation, culminating in the execution phase of apoptosis.87558-0/fulltext)^[44] In apoptotic cells, sphingomyelin hydrolysis on the outer leaflet of the plasma membrane contributes to the exposure of phosphatidylserine (PS), which serves as a primary "eat-me" signal for phagocytic clearance. The accumulation of ceramide from sphingomyelin breakdown disrupts membrane asymmetry via activation of scramblases like Xkr8, promoting PS translocation to the outer leaflet and facilitating recognition by phagocytes expressing receptors such as TIM-4 or Stabilin-2.^[45]^[46] This process ensures efficient removal of apoptotic bodies without eliciting inflammation, linking sphingomyelin metabolism directly to post-apoptotic engulfment.^[47] While ceramide predominantly drives pro-apoptotic pathways, intact sphingomyelin can exert anti-apoptotic effects by stabilizing membrane domains that support anti-apoptotic proteins like Bcl-2. In certain cellular contexts, such as during mild stress, unhydrolyzed sphingomyelin maintains lipid raft integrity, preventing ceramide-induced dephosphorylation and inactivation of Bcl-2, thereby inhibiting MOMP and caspase activation.^[48] Sphingomyelin's involvement in programmed cell death is evident in both extrinsic and intrinsic pathways. In the extrinsic pathway, tumor necrosis factor-α (TNF-α) rapidly activates neutral and acid SMases, hydrolyzing sphingomyelin to ceramide and amplifying death receptor signaling through Fas-associated death domain (FADD) recruitment.^[49]^[50] In the intrinsic pathway, oxidative stress triggers ASMase activation, generating mitochondrial ceramide that sensitizes cells to Bax/Bak oligomerization and cytochrome c release.^[42]^[51] Experimental evidence underscores sphingomyelin's role, as inhibition of SMase activity blocks apoptosis in neurodegeneration models. For instance, pharmacological inhibition of neutral SMase in serum/glucose-deprived PC-12 neuronal cells prevents ceramide elevation, c-Jun phosphorylation, and caspase-3 activation, thereby rescuing cell viability.^[52] Similarly, ASMase inhibitors reduce ceramide-mediated neuronal loss and apoptotic signaling in Alzheimer's disease models by limiting reactive astrocyte-derived extracellular vesicles.^[53] These findings highlight SMase as a therapeutic target to modulate apoptosis in neurodegenerative contexts.^[54]

Formation and Function of Lipid Rafts

Sphingomyelin (SM), in complex with cholesterol, forms the core of lipid rafts, which are dynamic, nanometer-scale membrane microdomains characterized by a liquid-ordered (Lo) phase that contrasts with the surrounding liquid-disordered (Ld) fluid membrane.^[55] These domains arise from the preferential partitioning of SM and cholesterol, where SM's saturated acyl chains and high melting temperature (Tm) promote tight packing and phase separation from unsaturated phospholipids in the Ld phase.^[56] The interaction is stabilized by hydrogen bonding between SM's phosphocholine headgroups and van der Waals forces with cholesterol, leading to ordered assemblies that span both leaflets of the bilayer and exhibit elastic deformation while maintaining fluidity.^[57] Glycosylphosphatidylinositol (GPI)-anchored proteins, such as CD59, are recruited to these rafts through transient colocalization and codiffusion with SM, dependent on cholesterol and GPI anchorage, facilitating protein clustering on timescales of 12–50 ms.^[57] Lipid rafts serve as organizing platforms for diverse cellular functions, particularly in immune receptor signaling, where SM-enriched domains concentrate T-cell receptor (TCR) components upon activation, enabling rapid compartmentalization of signaling molecules like LAT and PKCθ into rafts for NF-κB and NFAT pathway initiation.^[58] In viral entry and replication, rafts act as entry portals and replication sites; for instance, hepatitis C virus (HCV) exploits SM-cholesterol rafts to form replication complexes, where SM is essential for maintaining the structural integrity of these membrane factories enriched in viral proteins and RNA.^[2] Recent studies confirm SM's critical role in RNA virus replication, including HCV, by providing host-specific SM species that support viral RNA-dependent RNA polymerase activity in raft-like Golgi membranes.^[59] Additionally, rafts facilitate endocytosis through clathrin-independent pathways, such as caveolar and flotillin-dependent mechanisms, where SM aids membrane curvature and cargo sorting for internalization of ligands like EGF.^[60] Disruption of raft integrity by SM depletion, often via sphingomyelinase treatment, impairs domain assembly and function, leading to reduced pathogen resistance; for example, SM removal from the plasma membrane inhibits influenza virus entry by destabilizing viral-host membrane fusion and decreases phagocytic uptake of fungi via Fcγ receptors.^[61] This depletion shifts membrane lipids toward disordered states, hindering trafficking and signaling efficiency.^[62] Experimentally, lipid rafts are visualized and isolated as detergent-resistant membranes (DRMs), which retain SM and cholesterol due to their insolubility in non-ionic detergents like Triton X-100 at 4°C, serving as a biochemical proxy despite not fully recapitulating native dynamics.^[63]

Clinical and Pathological Aspects

Associated Diseases and Disorders

Sphingomyelin dysregulation is prominently implicated in Niemann-Pick disease, a lysosomal storage disorder caused by deficiency of acid sphingomyelinase (ASM), leading to progressive accumulation of sphingomyelin and its precursors in lysosomes across various tissues.^[64] In type A, severe ASM deficiency results in early-onset neurodegeneration, characterized by neuronal loss and progressive psychomotor deterioration, often fatal by early childhood, while type B manifests primarily as visceral involvement with hepatosplenomegaly, pulmonary infiltration, and milder neurological symptoms. This accumulation disrupts lysosomal function and cellular homeostasis, contributing to foam cell formation in affected organs.^[65] In atherosclerosis, elevated sphingomyelin levels within arterial plaques enhance vascular inflammation and promote foam cell formation through activation of sphingomyelinases, which hydrolyze sphingomyelin to generate ceramide, a pro-inflammatory mediator that exacerbates endothelial dysfunction and lipid retention.^[66] The sphingomyelin-ceramide axis facilitates macrophage lipid uptake and oxidative stress in the vessel wall, accelerating plaque progression and instability.^[67] Neutral sphingomyelinase-2, in particular, drives ceramide production in response to inflammatory signals, linking sphingomyelin metabolism to cardiometabolic pathology.^[68] Alterations in sphingomyelin metabolism contribute to neurological disorders such as Alzheimer's disease, where disrupted sphingomyelin levels in lipid rafts impair amyloid-β processing and promote amyloid plaque formation by altering membrane fluidity and protein trafficking.^[69] In Alzheimer's, sphingomyelin synthase disruption leads to intracellular amyloid-β accumulation and cognitive deficits, highlighting sphingomyelin's role in raft-mediated amyloidogenic pathways.^[70] For Parkinson's disease, elevated brain sphingomyelin correlates with disease duration and progression, potentially exacerbating mitochondrial dysfunction through ceramide-mediated impairment of energy metabolism and α-synuclein aggregation.^[71] Recent lipid profiling studies indicate sphingomyelin pathway dysregulation contributes to mitochondrial bioenergetic failure in Parkinson's, supporting its association with neuronal vulnerability.^[72] Sphingomyelin plays a role in metabolic diseases, including obesity and type 2 diabetes, where adipose tissue sphingomyelin influences insulin signaling by modulating membrane raft composition and ceramide generation, thereby promoting insulin resistance.^[73] In obesity, altered sphingomyelin levels in skeletal muscle and serum exacerbate lipid-induced inflammation and impaired glucose uptake, linking high-fat diets to metabolic dysfunction.^[74] Dyslipidemia associated with elevated circulating sphingomyelin species increases cardiovascular risk by fostering atherogenic lipoprotein profiles and endothelial inflammation.^[75] Infectious diseases involve sphingomyelin in viral replication, as seen with hepatitis C virus (HCV), where sphingomyelin is essential for the RNA replicase complex structure and activates viral polymerase activity, facilitating persistent infection.^[76] Inhibition of sphingomyelin synthesis disrupts HCV replication by targeting lipid-dependent viral assembly.^[77] For HIV, sphingomyelin enrichment in the viral envelope supports glycoprotein incorporation and membrane fusion, with neutral sphingomyelinase-2 inhibition impairing virion production and infectivity.^[78] HIV-1 Gag reorganizes host sphingomyelin-rich domains to optimize envelope formation, underscoring sphingomyelin's role in viral egress.^[79]

Therapeutic and Dietary Implications

Enzyme replacement therapy with olipudase alfa (Xenpozyme), a recombinant acid sphingomyelinase, has been approved for treating non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD), including Niemann-Pick disease type B, demonstrating improvements in lung function and reduced spleen and liver volumes in clinical trials.^[80] Real-world data from 2024-2025 confirm sustained benefits in adult patients, with enhanced quality of life and manageable infusion-related reactions.^[81] Inhibitors of sphingomyelin synthase (SMS), such as those targeting SMS2, show preclinical promise in cancer by reducing tumor stemness and promoting ceramide accumulation, particularly in breast cancer models where SMS2 overexpression confers chemotherapy resistance.^[82] Dietary sphingomyelin, abundant in milk and eggs, enhances intestinal barrier function by upregulating tight junction proteins and modulating gut microbiota composition, thereby reducing permeability in high-fat diet models.^[5] It also inhibits cholesterol absorption in the gut, lowering serum LDL levels more effectively from milk sources than eggs in rat studies.^[83] Animal models, including rabbits with hypercholesterolemia, indicate that dietary sphingomyelin attenuates atherosclerosis progression by decreasing aortic plaque formation and sphingomyelin enrichment in arterial walls.^[84] Supplementation with sphingomyelin combined with vitamin D3 exhibits neuroprotective effects in rabbit models, increasing glial fibrillary acidic protein expression and promoting brain cell differentiation as observed in 2025 studies.^[85] In obesity contexts, sphingomyelin supplements regulate gut microbiota to improve lipid metabolism and reduce inflammation in high-fat diet-fed mice, potentially mitigating weight gain and insulin resistance.^[86] Emerging gene therapies using adeno-associated viral vectors to deliver acid sphingomyelinase have shown efficacy in preclinical Niemann-Pick models by correcting lysosomal storage and reducing sphingomyelin accumulation. Sphingosine-1-phosphate (S1P) receptor modulators, such as fingolimod and siponimod—analogs derived from sphingomyelin metabolism—reduce relapse rates and delay progression in relapsing multiple sclerosis through lymphocyte sequestration.^[87] Ongoing preclinical and early-phase investigations target sphingomyelin pathways in Alzheimer's disease, with neutral sphingomyelinase-2 inhibitors like PDDC reducing tau pathology and ceramide-induced neurodegeneration in mouse models as of 2024 updates.^[88] For cardiovascular disease, acid sphingomyelinase inhibitors are under exploration to mitigate ceramide-driven endothelial dysfunction, supported by 2025 reviews of their role in atherosclerosis, though no large-scale human trials have reported results by late 2025.^[89]

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A Comparative Study of the Lipids of the Vertebrate Central Nervous ...
The finding that cerebroside, cholesterol and sphingomyelin, and not lecithin and kephalin, occur in a higher concentration in the brains of mammals than in the ...
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Dietary Sphingomyelin Metabolism and Roles in Gut Health and ...
Sphingomyelin (SM) is a widely occurring sphingolipid that is a major plasma membrane constituent. Milk and dairy products are rich SM sources, and human milk ...
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Role of lipid composition on the structural and mechanical features ...
May 29, 2019 · A sphingomyelin/phospholipid/cholesterol bilayer is used to mimic a plasma membrane and a galactosylceramide/phospholipid/cholesterol bilayer ...<|control11|><|separator|>
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Efficient replacement of plasma membrane outer leaflet ... - PNAS
Nov 21, 2016 · In general, the outer membrane leaflet in mammalian cells is composed primarily of sphingomyelin (SM) and phosphatidyl choline (PC). In contrast ...
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https://www.pnas.org/doi/10.1073/pnas.1610705113
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https://doi.org/10.1016/j.bbamem.2020.183382
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Identification of a functional role for lipid asymmetry in ... - PNAS
We documented that maintenance of asymmetric distribution of phospholipids resulted in improved membrane mechanical stability.
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Acid sphingomyelinase regulates glucose and lipid metabolism in ...
Ceramide induces insulin resistance by inactivation of AKT through protein phosphatase-2A and PKC-ζ (14, 15) or by inhibition of AKT translocation to the ...Missing: review | Show results with:review<|control11|><|separator|>
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Sphingosine 1-phosphate signalling - Company of Biologists journals
Jan 1, 2014 · S1P is a lipid mediator formed by the metabolism of sphingomyelin. In vertebrates, S1P is secreted into the extracellular environment and signals via G protein ...<|control11|><|separator|>
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Acid sphingomyelinase mediates 50-Hz magnetic field-induced EGF ...
Feb 26, 2016 · EGFR clustering, ASMase, and lipid rafts on cell membrane were analyzed using confocal microscopy after indirect immunofluorescence staining.Missing: integrin signaling
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Integrin Mechano-chemical Signaling Generates Plasma Membrane ...
Jun 13, 2019 · Integrin Mechano-chemical Signaling Generates Plasma Membrane Nanodomains that Promote Cell Spreading ... sphingomyelin (exo-scSM; H) and re- ...
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Sphingomyelin regulates the transcriptional machinery in nuclear ...
Aug 29, 2025 · Nuclear lipid microdomains rich in sphingomyelin and cholesterol content regulate double-stranded exonuclease-resistant RNA.
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The critical roles of bioactive sphingolipids in inflammation - PMC
Jul 11, 2025 · It should also be pointed out that sphingolipid-activated pathways may cross-talk with other metabolic or cell signaling pathways that control ...
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The Cross-Talk Between Sphingolipids and Insulin-Like Growth ...
Moreover, accumulating evidence suggests extensive links between sphingolipid signaling and the insulin-like growth factor I (IGF-I)-Akt-mTOR pathway (IIS), ...
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Stress-induced Apoptosis and the Sphingomyelin Pathway - PubMed
The present review focuses on mechanisms of activation of ASMase and on ceramide signaling of the apoptotic response.
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Lysosomal ceramide generated by acid sphingomyelinase triggers ...
Apr 9, 2015 · These findings suggest that lysosomal ceramide produced by ASM mediates XIAP degradation by activation of cytosolic CTSB and caspase-dependent apoptosis.
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Mitochondrial cytochrome c release precedes transmembrane ...
Mitochondrial cytochrome c release precedes transmembrane depolarisation and caspase-3 activation during ceramide-induced apoptosis of Jurkat T cells.
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Sphingomyelin Hydrolysis to Ceramide during the Execution Phase ...
We show that, as a consequence of the loss of PL asymmetry, SM moves from the outer to the inner leaflet of the plasma membrane, where it serves as a substrate ...
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Aug 27, 2013 · Cell surface PS exposure is a classic feature of apoptotic cells and acts as an “eat me” signal allowing phagocytosis of post-apoptotic bodies.
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Getting to the Outer Leaflet: Physiology of Phosphatidylserine ...
Mar 2, 2016 · This review discusses what is known about the mechanism of PS exposure at the surface of the plasma membrane of cells, how actors in the ...
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Anti-apoptotic Bcl-2 Family Proteins Disassemble Ceramide Channels
In fact, inhibitors of sphingolipid metabolism that prevented ceramide synthesis after UV irradiation also prevented apoptosis (20). MOM permeabilization and ...
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Tumor Necrosis Factor-α Activates the Sphingomyelin Signal ...
TNF-α signaling may involve sphingomyelin hydrolysis to ceramide by a sphingomyelinase and stimulation of a ceramide-activated protein kinase.
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Involvement of FAN in TNF-induced apoptosis - JCI
... TNF-induced ceramide generation from sphingomyelin hydrolysis and reduces caspase processing, thus markedly inhibiting TNF-triggered apoptosis. However, the ...
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Rapid Activation of Neutral Sphingomyelinase by Hypoxia ...
Alterations of ceramide and JNK activities have been associated with ischemia and reperfusion of both kidney and heart, and may be involved in apoptosis ...
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Inhibition of sphingomyelinase activity helps to prevent neuron ...
SMAs inhibited the enhanced N-SMase activity in the serum/glucose-deprived PC-12 cells, and thereby suppressed the apoptotic sequence: ceramide formation, c-Jun ...
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Inhibition of acid sphingomyelinase reduces reactive astrocyte ...
Aug 21, 2023 · Our study identifies A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.
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Identification of Novel Functional Inhibitors of Acid Sphingomyelinase
Inhibition of ASM results in anti-apoptotic, proliferative and anti-inflammatory effects. Furthermore, ASM could play a key role in the pathophysiology of ...
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https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023852
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Sphingomyelin distribution in lipid rafts of artificial monolayer ...
Mar 30, 2015 · Sphingomyelin (SM) and cholesterol (chol)-rich domains in cell membranes, called lipid rafts, are thought to have important biological functions ...Abstract · Sign Up For Pnas Alerts · Results
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Raft-based sphingomyelin interactions revealed by new fluorescent ...
Sphingomyelin (SM) has been proposed to form cholesterol-dependent raft domains and sphingolipid domains in the plasma membrane (PM). How SM contributes to the ...
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The role of lipid rafts in signalling and membrane trafficking in T ...
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https://journals.biologists.com/jcs/article/114/22/3957/35497/The-role-of-lipid-rafts-in-signalling-and-membrane
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The role of lipid rafts in vesicle formation | Journal of Cell Science
May 9, 2023 · Lipid rafts are involved in the formation of transport vesicles, endocytic vesicles, exocytic vesicles, synaptic vesicles and extracellular vesicles, as well ...Lipid--Lipid Interactions · Lipid--Protein Interactions · Rafts And Endocytic Vesicles
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Depletion of Host and Viral Sphingomyelin Impairs Influenza Virus ...
Apr 29, 2020 · Depleting plasma membrane SM by exogenous bacterial SMase (bSMase) impaired virus infection and reduced virus entry, whereas exogenous SM enhanced infection.
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Sphingomyelin Depletion Impairs Anionic Phospholipid Inward ... - NIH
Overall, our data indicates that SM depletion led to a redistribution of anionic phospholipids across the plasma membrane, decreased lipid rafts, increased ...
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Detergent-resistant membranes and the protein composition of lipid ...
One biochemical definition of lipid rafts is their insolubility in non-ionic detergents at 4°C - a condition that yields detergent-resistant membranes (DRMs).
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Biochemical and imaging parameters in acid sphingomyelinase ...
Acid Sphingomyelinase Deficiency (ASMD), or Niemann-Pick type A/B disease, is a rare lipid storage disorder leading to accumulation of sphingomyelin and its ...Missing: AB | Show results with:AB
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[Acid sphingomyelinase deficiency: A review] - PubMed
May 24, 2025 · Acid sphingomyelinase deficiency, formerly known as Niemann-Pick disease types B, A/B, and B, is a rare genetic disorder. It is an inherited ...Missing: AB | Show results with:AB
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Liver and skin histopathology in adults with acid sphingomyelinase ...
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Sphingolipids in Atherosclerosis: Chimeras in Structure and Function
Oct 8, 2022 · ... sphingomyelin (SM), lactosylceramide (LacCer), and ... In this review, we point out their specific roles in atherosclerosis ...
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Sphingomyelin metabolites in vascular cell signaling and ... - PubMed
Here we review the potential implication of the sphingomyelin/ceramide cycle in vascular cell signaling related to atherosclerosis, and more generally the ...
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Neutral sphingomyelinase-2 and cardiometabolic diseases - PubMed
... atherosclerosis, inflammation, nonalcoholic steatohepatitis, and cancer. Ceramides are produced by the hydrolysis of sphingomyelin ... In this review, we ...
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Alzheimer's Disease as a Membrane Disorder: Spatial Cross-Talk ...
Jul 18, 2019 · Alzheimer's Disease as a Membrane Disorder: Spatial Cross-Talk Among Beta-Amyloid Peptides, Nicotinic Acetylcholine Receptors and Lipid Rafts.
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Disruption of sphingomyelin synthase 2 gene alleviates cognitive ...
Jul 15, 2024 · Sphingomyelin in the membrane raft may serve as a novel target for AD drugs. Keywords: Alzheimer's disease; Intracellular amyloid β; Membrane ...
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A protective role of ABCA5 in response to elevated sphingomyelin ...
Jan 11, 2024 · We found that sphingomyelin levels were significantly increased in PD compared to controls and correlated with disease duration only in the ...
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Lipid pathway dysfunction is prevalent in patients with Parkinson's ...
Oct 21, 2022 · Lipid pathway dysfunction is prevalent in patients with Parkinson's disease ... mitochondrial function were the major metabolic pathways ...
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Altered levels of serum sphingomyelin and ceramide containing ...
Oct 20, 2014 · Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase.
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The role of skeletal muscle sphingolipids in the ... - PubMed
May 13, 2008 · There is evidence that intramyocellular lipids might be responsible for this process through inhibition of insulin signaling. One of the ...
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Associations of APOE variants with sphingomyelin and cholesterol ...
May 7, 2025 · ... sphingomyelin and cholesterol ... dyslipidemia, which are important risk factors for the development of cardiovascular diseases.
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Sphingomyelin Is Essential for the Structure and Function ... - PubMed
Nov 9, 2020 · Sphingomyelin (SM) is required for hepatitis C virus (HCV) replication, but the mechanism of SM involvement remains poorly understood.
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Sphingomyelin activates hepatitis C virus RNA polymerase in a ...
Hepatitis C virus (HCV) replication and infection depend on the lipid components of the cell, and replication is inhibited by inhibitors of sphingomyelin ...
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Inhibition of neutral sphingomyelinase 2 impairs HIV-1 envelope ...
Jul 11, 2023 · Here, we provide evidence that the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) interacts with HIV-1 Gag and through the ...
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HIV-1 Gag targeting to the plasma membrane reorganizes ... - PubMed
HIV-1 Gag targeting to the plasma membrane reorganizes sphingomyelin-rich and cholesterol-rich lipid domains. Nat Commun. 2023 Nov 21;14(1):7353. doi: ...
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XenpozymeTM (olipudase alfa-rpcp) approved by FDA as first ...
Aug 31, 2022 · Xenpozyme is the first therapy indicated specifically for the treatment of ASMD, and is currently the only approved treatment for this disease.
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Real-life impacts of olipudase alfa: experiences of adults receiving ...
Sep 30, 2025 · Olipudase alfa, an enzyme replacement therapy (ERT), has recently been approved in several countries to treat the non-central nervous system ...
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Sphingomyelin synthase 2 promotes the stemness of breast cancer ...
Jan 29, 2024 · SMS2 increased the stemness of breast cancer cells via NF-κB signaling pathway, leading to resistance to the chemotherapeutic drug ADR.
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Milk sphingomyelin is more effective than egg ... - PubMed
The results indicate that both milk and egg SM markedly inhibit the absorption of cholesterol, fat, and other lipids. However, milk SM is a more potent ...Missing: barrier atherosclerosis rabbit 2025
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Sphingomyelin and other phospholipid metabolism in the rabbit ...
Hypercholesterolemia induces atheroma formation, and the concentration of sphingomyelin is increased compared with that in the normal aortic intima-media.
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Effect of Sphingomyelin and Vitamin D3 Intake on the Rabbit Brain
Apr 1, 2025 · In summary, we found very positive effects of SM + VD3 in the brain. In general, the differentiative markers of intestine and liver cells did ...
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The impacts of dietary sphingomyelin supplementation on metabolic ...
Feb 23, 2024 · Milk sphingomyelin improves lipid metabolism and alters gut microbiota in high fat diet-fed mice. J Nutr Biochem. (2016) 30:93–101. doi ...
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Optimization of systemic AAV9 gene therapy in Niemann-Pick ...
Jun 8, 2024 · This autosomal recessive lysosomal storage disorder is marked by unesterified cholesterol and sphingolipid accumulation in the lysosome, the ...
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An update on the use of sphingosine 1-phosphate receptor ...
Mar 22, 2023 · S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS.
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Neutral sphingomyelinase 2: A promising drug target for CNS disease
Chapter Three - Neutral sphingomyelinase 2: A promising drug target for CNS disease. Author links open overlay panel. Meixiang Huang a ...
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Emerging roles of the acid sphingomyelinase/ceramide pathway in ...
Feb 26, 2025 · This review synthesizes recent research on the biological functions, regulatory mechanisms, and targeted therapies related to the ASMase/Cer pathway in ...