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Squalene

Squalene is a triterpenoid hydrocarbon with the molecular formula C₃₀H₅₀, consisting of six isoprene units linked tail-to-tail, that functions as a crucial intermediate in the sterol biosynthetic pathway leading to cholesterol and other steroids in eukaryotes.^[1]^[2] It appears as a colorless, highly unsaturated oil with six double bonds, rendering it resistant to lipid peroxidation and conferring antioxidant properties.^[1]^[3] First isolated in abundance from shark liver oil—hence its name derived from the Latin squalus for shark—squalene is also produced endogenously in human sebum and liver, and occurs in plant sources such as olive oil and amaranth seeds.^[3]^[4] In biosynthesis, it forms via the enzyme squalene synthase from two molecules of farnesyl pyrophosphate, followed by epoxidation and cyclization to yield lanosterol, the precursor to cholesterol.^[5] Industrially, squalene is extracted for use as an emollient in cosmetics due to its biocompatibility with skin lipids, as a vehicle in pharmaceuticals, and as a component of oil-in-water emulsion adjuvants like MF59 in certain influenza vaccines to potentiate immune responses without inducing autoimmunity in empirical studies.^[1]^[2] Its role in cholesterol homeostasis has drawn research interest, with dysregulation linked to conditions like hypercholesterolemia, though squalene supplementation shows no causal elevation of serum cholesterol levels in controlled trials.^[6]^[2]

Chemical Structure and Properties

Molecular Composition and Structure

Squalene is a triterpenoid hydrocarbon with the molecular formula C₃₀H₅₀, consisting of a linear 30-carbon chain assembled from six isoprene (C₅H₈) units.^[1]^[7]^[8] This structure features six isolated carbon-carbon double bonds, specifically in the all-E configuration at positions 2, 6, 10, 14, 18, and 22, along with methyl substituents at carbons 2, 6, 10, 15, 19, and 23, yielding the systematic name (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene.^[9] The molecule's architecture derives from the tail-to-tail linkage of two farnesyl (C₁₅) moieties, distinguishing it from typical head-to-tail isoprenoid polymers and conferring a central symmetric bond between carbons 15 and 15'.^[10]^[11] This arrangement positions the double bonds in an isolated, non-conjugated manner, contributing to squalene's relative chemical stability compared to more unsaturated hydrocarbons while maintaining reactivity at the alkene sites.^[5] In relation to sterols, squalene functions as the immediate acyclic precursor to cholesterol, undergoing epoxidation at the central double bond by squalene epoxidase (also known as squalene monooxygenase) to form 2,3-oxidosqualene, which enables enzymatic cyclization into polycyclic structures like lanosterol.^[12]^[13] This transformation highlights squalene's structural suitability as a linear scaffold for folding into the tetracyclic sterol framework, with its isoprenoid branching facilitating the necessary stereochemistry.^[14]

Physical and Chemical Characteristics

Squalene is a colorless to pale yellow, odorless liquid at room temperature, exhibiting a faint oily consistency due to its nonpolar hydrocarbon nature.^[1] Its melting point is -75 °C, allowing it to remain fluid under typical ambient conditions, while the boiling point is approximately 285 °C at 25 mm Hg pressure.^[15] The density measures 0.858 g/mL at 25 °C, reflecting its lightweight, hydrophobic profile.^[15] Squalene demonstrates low water solubility, typically less than 0.1 mg/L, but high solubility in nonpolar organic solvents such as hexane and chloroform.^[1] Chemically, squalene's structure includes six isolated trans carbon-carbon double bonds along its linear C₃₀H₅₀ chain, which confer lipophilicity and moderate resistance to auto-oxidation under inert conditions compared to conjugated polyenes, though the unsaturation renders it reactive toward strong oxidants like ozone and singlet oxygen via ene reactions at the double bonds.^[1]^[16] This reactivity leads to hydroperoxide formation upon exposure to reactive oxygen species, but purified squalene maintains stability in anaerobic storage, with minimal peroxidation at room temperature over months.^[17] Its refractive index is around 1.495, aiding optical characterization in analytical settings.^[18] Purity and identity are verified spectroscopically; ¹H NMR shows distinct signals for allylic methyl protons at δ 1.6-1.7 ppm and olefinic protons at δ 5.1-5.2 ppm, while mass spectrometry yields a molecular ion at m/z 410 for the intact molecule, with fragmentation patterns confirming the isoprenoid units.^[19]^[1] These signatures enable quantitative analysis via techniques like GC-MS, distinguishing squalene from oxidized derivatives or isomers.^[20]

Biological Significance

Biosynthetic Role in Triterpenoids and Steroids

Squalene serves as a central intermediate in the mevalonate pathway, where it is synthesized through the head-to-head condensation of two molecules of farnesyl pyrophosphate (FPP), catalyzed by squalene synthase (SQS), also known as farnesyl-diphosphate farnesyltransferase.^[21] ^[6] This reaction represents the first committed step dedicated to sterol biosynthesis, branching from the broader isoprenoid pathway and requiring NADPH as a cofactor to reduce the intermediate presqualene diphosphate.^[22] In eukaryotes, this enzymatic step commits precursors toward the production of triterpenoids, including steroids. Subsequent to its formation, squalene undergoes epoxidation at the 2,3-position by squalene epoxidase (also termed squalene monooxygenase), yielding (3S)-2,3-oxidosqualene.^[23] This epoxide is then cyclized by oxidosqualene cyclase, such as lanosterol synthase in animals, to form lanosterol, the foundational tetracyclic sterol structure.^[24] ^[25] Lanosterol undergoes multiple demethylations, reductions, and migrations to yield cholesterol, which serves as the precursor for bile acids, vitamin D, and steroid hormones.^[23] In plants and some protists, the cyclase produces cycloartenol instead, leading to phytosterols, but the squalene-to-epoxide-to-cyclic triterpenoid sequence remains conserved.^[24] Squalene's accumulation and flux are tightly regulated to maintain sterol homeostasis, with excess cholesterol promoting the degradation of squalene epoxidase via Insig-mediated ubiquitination, thereby preventing overproduction of sterols.^[26] Upstream, high sterol levels feedback-inhibit HMG-CoA reductase, the rate-limiting enzyme in mevalonate production, indirectly controlling squalene synthesis through reduced FPP availability.^[27] ^[28] This multilayered regulation ensures balanced sterol levels essential for membrane integrity and signaling, with disruptions linked to disorders like squalene synthase deficiency.^[29]

Natural Occurrence and Physiological Functions

Squalene is found in high concentrations in the liver oil of certain deep-sea shark species, where it constitutes 50-82% of the total oil content, serving as a major lipid component for buoyancy and energy storage.^[30] In humans, it comprises approximately 12% of the lipid fraction in sebum secreted by sebaceous glands, with lower levels present transiently in most other tissues as a cholesterol precursor.^[31] Plant sources contain squalene at much lower levels, such as 0.1-0.7% of total lipids in extra virgin olive oil and trace amounts in oils from amaranth seeds or rice bran.^[32] Physiologically, squalene functions primarily as an antioxidant through direct scavenging of reactive oxygen species and free radicals, thereby inhibiting lipid peroxidation in cellular membranes and skin surface lipids.^[2] This mechanism protects unsaturated lipids from oxidative damage, particularly under environmental stressors like UV radiation, where squalene's polyisoprenoid structure enables efficient quenching of singlet oxygen and peroxyl radicals.^[33] In skin, its presence in sebum supports barrier integrity by reducing transepidermal water loss and stabilizing the stratum corneum against irritants, as demonstrated in ex vivo models of epidermal lipid protection.^[16] In vitro studies further indicate squalene's capacity to modulate inflammation by suppressing pro-inflammatory mediators, though these effects are concentration-dependent and primarily observed at pharmacological levels rather than endogenous ones.^[34] Its accumulation in sebaceous glands correlates with elevated local concentrations, potentially enhancing local antioxidant defense without systemic accumulation due to rapid downstream metabolism in other tissues.^[35] Empirical data from lipid oxidation assays confirm squalene's superior efficacy compared to other sebum components in preventing hydroperoxide formation.^[36]

History and Discovery

Initial Isolation from Natural Sources

Squalene was recognized in traditional Japanese medicine long before its chemical identification, with shark liver oil employed for wound healing and as a general tonic due to its purported restorative properties. Historical records indicate that coastal communities in Japan utilized oils extracted from deep-sea sharks, such as those from the genus Squalus, to treat injuries and bolster resilience against infections, attributing efficacy to the oil's emollient and protective qualities on skin and mucous membranes.^[37] This pre-scientific application stemmed from empirical observations of the oil's stability and biocompatibility, though without knowledge of its active components.^[38] The compound was first isolated in pure form in 1906 by Japanese chemist Mitsumaru Tsujimoto, working at the Tokyo Industrial Testing Station, from liver oil of sharks belonging to the Squalus genus. Tsujimoto separated the substance through fractional distillation and saponification of the unsaponifiable fraction, identifying it as a colorless, odorless liquid hydrocarbon with six double bonds, comprising up to 40% of certain shark liver oils. He named it "squalene" deriving from Squalus, reflecting its primary natural source, and characterized it preliminarily as an unsaturated triterpene-like molecule with the empirical formula approximating C₃₀H₅₀.^[1]^[39]^[3] Early 20th-century analyses further defined squalene's properties as a highly unsaturated aliphatic hydrocarbon. In 1926, British biochemist Harold John Channon conducted experiments confirming its chemical stability and biological inertness in rat liver metabolism, while proposing its role in lipid unsaponifiables; concurrent work by Ian Morris Heilbron and collaborators refined the structural formula to C₃₀H₅₀, establishing it as a tail-to-tail linked dimer of farnesyl units through hydrogenation and ozonolysis studies. These characterizations relied on classical organic techniques, distinguishing squalene from related sterol precursors and highlighting its prevalence in elasmobranch livers as an evolutionary adaptation for buoyancy via low-density lipids.^[40]^[41]

Key Scientific and Industrial Developments

In the 1950s, Konrad Bloch and colleagues elucidated key steps in the biosynthetic pathway from acetate to squalene and onward to cholesterol, demonstrating squalene's central role as a linear precursor in sterol formation through isotopic labeling experiments in liver and yeast systems.^[42] This work, building on earlier partial pathways, clarified the cyclization of squalene to lanosterol under anaerobic conditions in some organisms, earning Bloch the 1964 Nobel Prize in Physiology or Medicine (shared with Feodor Lynen) for foundational insights into cholesterol metabolism regulation.^[43] Amid concerns over shark overfishing in the late 20th century, industrial production pivoted in the 1990s toward plant-derived squalene, particularly from olive oil refining byproducts, which contain 0.1-0.7% squalene and offered a scalable alternative to animal liver extraction.^[39] This shift addressed depletion of deep-sea shark populations, where liver oil historically supplied up to 90% of commercial squalene, enabling sustained yields without ecological strain.^[44] The development of squalene-based emulsions advanced in the 1990s, culminating in the 1997 European approval of MF59, an oil-in-water formulation containing 4.3% squalene, as the first novel adjuvant licensed for human vaccines since aluminum salts.^[45] This milestone stemmed from empirical trials showing enhanced immune responses via local innate signaling, distinct from antigen-specific mechanisms.^[46] In the 2020s, metabolic engineering has yielded high-titer microbial production, with CRISPR-edited Saccharomyces cerevisiae strains achieving squalene titers exceeding 50 g/L through flux redirection via mevalonate pathway overexpression and cofactor balancing.^[47] Similarly, engineered Yarrowia lipolytica platforms have reported 32-51 g/L under fed-batch conditions, prioritizing NADPH-dependent reductases and squalene synthase optimization for industrial viability.^[48] These advances enable cost-competitive biosynthesis from glucose or lignocellulosic feedstocks, reducing reliance on natural extracts.^[49]

Production Methods

Traditional Animal Sourcing

Traditionally, squalene has been extracted primarily from the liver oil of deep-sea sharks, particularly species in the genus Centrophorus such as the smallfin gulper shark (Centrophorus moluccensis), where it constitutes 40-83% of the liver mass or 49-89% of the extracted oil.^[50]^[51] These sharks' livers, comprising up to 29% of body weight, yield high volumes of oil through grinding, cooking, and pressing, followed by distillation under vacuum at 200-300°C to isolate squalene with over 98% purity in a single step.^[52]^[53] This method leverages the economic advantage of squalene's abundance in these organs, providing both high purity and substantial quantities compared to other natural sources.^[54] Historical extraction intensified during World War II, when shark liver oil served as a substitute for cod liver oil to supply vitamin A amid blockades disrupting traditional fisheries, with U.S. coastal operations processing thousands of livers daily.^[55] Post-1950s, focus shifted to squalene itself for industrial applications, driven by its characterization and ease of isolation from shark livers containing 40-80% of the compound.^[38] Global production peaked in the late 20th century, with annual demand reaching 1,000-2,000 tons, necessitating the harvest of approximately 3,000 sharks per ton due to liver oil yields of 30-100% squalene content after processing.^[56]^[57] This sourcing has contributed to documented declines in deep-sea shark populations, as reported by the Food and Agriculture Organization (FAO), with overfishing for liver oil—often as targeted catches or bycatch—exacerbating vulnerabilities in slow-reproducing species like Centrophorus spp., where stocks have shown significant reductions from historical levels.^[58]^[59] FAO assessments indicate that such harvesting, combined with the sharks' life histories, has led to unsustainable pressures, though exact bycatch figures vary by region and fishery.^[60] Despite these impacts, animal-derived squalene remains valued for its established yield efficiency in traditional processing.^[30]

Biosynthetic Pathways in Organisms

In eukaryotes such as animals and fungi, squalene biosynthesis predominantly occurs via the mevalonate (MVA) pathway, starting from acetyl-CoA and proceeding through intermediates like 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), mevalonate, isopentenyl pyrophosphate (IPP), and dimethylallyl pyrophosphate (DMAPP), ultimately yielding farnesyl pyrophosphate (FPP) which is dimerized by squalene synthase to form squalene.^[61] In contrast, prokaryotes including most bacteria and cyanobacteria utilize the methylerythritol phosphate (MEP) pathway for isoprenoid precursors, converting glyceraldehyde-3-phosphate and pyruvate into IPP and DMAPP, with squalene formed similarly from FPP, though plants possess both pathways, employing MEP in plastids for specific terpenoids while MVA operates cytosolically.^[61] ^[62] Key enzymatic steps include the condensation of IPP and DMAPP by geranylgeranyl pyrophosphate synthase and farnesyl pyrophosphate synthase (FPS) to produce FPP, followed by NADPH-dependent reduction and head-to-head coupling by squalene synthase (SQS), with HMG-CoA reductase often serving as the primary rate-limiting enzyme in the MVA pathway due to its regulatory feedback inhibition, while FPS activity and FPP availability represent bottlenecks in both pathways, limiting flux to squalene.^[63] ^[5] Overexpression of rate-limiting enzymes such as HMG-CoA reductase, FPS, and isomerase (IDI) in model organisms has empirically enhanced pathway flux; for instance, in engineered Saccharomyces cerevisiae, co-expression of these genes alongside squalene synthase boosts intracellular squalene accumulation by alleviating precursor shortages.^[64] ^[48] Comparative production yields highlight pathway efficiencies: wild-type bacteria via MEP typically achieve less than 1 g/L squalene in lab cultures due to competing isoprenoid sinks and low precursor pools, whereas engineered yeasts leveraging MVA modifications have attained 5-11 g/L in shake-flask and bioreactor scales through targeted gene amplifications and cofactor balancing, demonstrating superior flux control in eukaryotic chassis despite inherent regulatory constraints.^[47] ^[65] These enhancements underscore causal dependencies on upstream precursor supply and enzymatic kinetics, with bottlenecks like NADPH availability further tunable via metabolic rerouting in microbial hosts.^[64]

Modern Industrial and Sustainable Alternatives

Engineered microbial fermentation represents a primary sustainable alternative to traditional squalene sourcing, with yeast strains like Yarrowia lipolytica and Saccharomyces cerevisiae achieving high titers through metabolic pathway optimization and subcellular compartmentalization. Recent advances in 2023–2024, including peroxisomal and dual cytoplasmic-peroxisomal targeting of squalene synthase, have boosted production to over 20 g/L; for example, peroxisomal engineering in S. cerevisiae yielded 32.8 g/L from glucose in fed-batch processes, while cytoplasmic-peroxisomal strategies in Y. lipolytica reached 51.2 g/L.^[66]^[67] These improvements enhance flux through the mevalonate pathway by localizing enzymes near precursors like farnesyl pyrophosphate, improving yields by 2–5 fold over cytosolic-only expression.^[47] Scalability is demonstrated in 5-L bioreactors, with fed-batch feeding of glucose or acetate supporting cell densities over 100 g/L dry weight.^[66] Algal fermentation using Thraustochytrium sp. provides another microbial route, leveraging native high squalene accumulation in lipid bodies. Optimized fed-batch cultures have attained 13.73 g/L titers at biomass concentrations of 96 g/L, with genetic tweaks to carbon flux increasing squalene content to 14% of dry weight.^[68] Process costs remain higher than yeast due to saltwater media requirements and slower growth, but co-production with polyunsaturated fatty acids like DHA adds value for integrated biorefineries.^[69] Biotech-derived plant feedstocks, such as sugarcane fermented via engineered yeast, enable large-scale production; Amyris's process, operational since 2022 in Brazil, converts sugarcane syrup to squalene at industrial volumes committed through 2023.^[70]^[71] Olive-derived extraction from oil or pomace offers a non-fermentative alternative, using alkaline saponification or supercritical fluids to isolate 97.5% purity squalene at yields of 500–600 mg/100 g oil.^[39]^[72] These methods reduce reliance on shark liver oil, historically cheaper at extraction costs under $50/kg versus $100–500/kg for microbial routes, though yield gains are closing the gap.^[52] Sustainability metrics include 50–70% lower CO2 emissions for fermentation versus fishing and refining, supporting market shifts where plant and microbial sources are projected to exceed animal-derived by volume growth rates of 6–8% annually through 2028.^[53]^[73]

Applications and Uses

In Cosmetics and Emollients

Squalene functions as an emollient and antioxidant in cosmetic formulations, including creams, lotions, and serums, where it is typically used at concentrations of 0.1% to 5% to provide hydration and protect against oxidative stress.^[2]^[74] As a natural component of human sebum comprising approximately 12-13% of its lipids, squalene mimics the skin's endogenous oils, enabling non-comedogenic moisture retention by forming a lightweight barrier that reduces transepidermal water loss without pore occlusion.^[2]^[75] Due to squalene's polyunsaturated structure, which renders it prone to rapid oxidation and rancidity in formulations, the saturated derivative squalane—produced via hydrogenation—is predominantly utilized instead, offering comparable emolliency and biocompatibility with superior stability for extended shelf life and skin application.^[74]^[76] The Cosmetic Ingredient Review Expert Panel, in its 2019 safety assessment, concluded that both squalene and squalane are safe as cosmetic ingredients in practices of use and concentration described therein, including squalane at levels up to 100% in leave-on products like pure oils. In anti-aging cosmetics, squalane enhances the percutaneous absorption of active compounds such as retinoids, improving their delivery to deeper skin layers while mitigating irritation through its occlusive and lubricating properties, as evidenced in vehicle formulations for retinol and granactive retinoids.^[2]^[77] This penetration-enhancing effect, combined with squalane's antioxidant capacity to neutralize free radicals, supports its prevalence in products targeting fine lines, elasticity, and barrier repair.^[75]^[78]

As Vaccine and Pharmaceutical Adjuvants

Squalene serves as the primary oil phase in oil-in-water emulsion adjuvants, such as MF59 and AS03, which enhance vaccine immunogenicity by promoting antigen uptake and innate immune activation at the injection site.^[45] MF59, formulated with 4.3% squalene emulsified using Tween 80 and Span 85, was first approved in 1997 for use in an influenza vaccine (Fluad) targeting adults aged 65 and older in Italy, enabling effective responses with reduced antigen doses.^[79] AS03, containing approximately 10 mg squalene per dose along with α-tocopherol and polysorbate 80, was deployed in H1N1 influenza vaccines during the 2009 pandemic, facilitating rapid production and dose-sparing through heightened antibody production.^[80] These emulsions create submicron droplets (around 165 nm for MF59) that disperse locally, recruiting immune cells without persistent depot formation, unlike traditional adjuvants.^[81] The mechanistic role of squalene in these emulsions involves stimulating transient innate immune responses, including ATP release from muscle cells and upregulation of chemokines like CXCL10, which drive monocyte and dendritic cell influx for improved antigen presentation.^[82] This activation enhances both quantitative and qualitative aspects of adaptive immunity, with squalene's biodegradability ensuring rapid clearance while the emulsion structure synergizes surfactants like Tween 80 and Span 85 to stabilize droplets and modulate local inflammation.^[83] Empirical studies demonstrate that MF59-adjuvanted influenza vaccines elicit antibody titers sufficient for seroprotection at antigen doses 65- to 80-fold lower than non-adjuvanted formulations, reflecting squalene's contribution to efficient T cell priming and germinal center formation.^[84] Dose-response data indicate that 5-10 mg squalene per vaccine dose (e.g., 9.75 mg in MF59) consistently amplifies hemagglutination inhibition titers by factors enabling broader strain coverage, as observed in trials where adjuvanted vaccines achieved protective levels with 3.75-15 μg hemagglutinin antigen.^[85] These effects extend to balanced Th1/Th2 cytokine profiles, with enhanced IgG2 subtypes linked to squalene-driven follicular helper T cell activity, supporting robust humoral responses in diverse populations.^[86] Over 100 million doses of MF59-adjuvanted vaccines have been administered globally since initial approvals, with immunogenicity confirmed across seasonal and pandemic strains.^[79]

Other Industrial and Biomedical Applications

Squalene has been incorporated into liposomes and lipid nanoparticles to enhance drug delivery systems, exploiting its biocompatibility and ability to form stable emulsions with hydrophobic drugs. For instance, asolectin-squalene liposomes have been characterized for embedding and releasing hydrophobic molecules to target cells, as demonstrated in biophysical studies published in 2018.^[87] Similarly, squalene-conjugated gemcitabine nanoparticles, developed in a 2017 study, interact with circulating lipoproteins to facilitate targeted delivery to cancer cells, improving pharmacokinetics over free drug forms.^[88] These formulations leverage squalene's natural lipid properties to stabilize nanoparticles for RNA and small-molecule therapeutics, with ongoing research highlighting its role as an excipient in self-assembling lipid systems.^[89] In cancer therapeutics, squalene-based nanoparticles have shown potential to augment antiproliferative effects, particularly when squalene is combined with therapeutic agents to exploit tumor lipid metabolism vulnerabilities. A 2024 study reported that squalene incorporation into nanoparticles enhanced cytotoxicity against breast cancer cells compared to squalene alone, attributing efficacy to squalene's interference with oxidative stress pathways in malignant tissues.^[90] Oxidation products of squalene, such as monohydroperoxides formed via singlet oxygen or free radical mechanisms, have been analyzed for their biological reactivity, though direct therapeutic applications remain exploratory and tied to squalene's broader antioxidant modulation in preclinical models.^[16] These approaches build on squalene's endogenous role as a cholesterol precursor, potentially disrupting sterol-dependent tumor growth without the enzyme inhibition seen in squalene epoxidase-targeted therapies.^[91] As a nutraceutical, squalene is marketed in food supplements for purported cholesterol modulation, drawing from its position in the sterol biosynthetic pathway. However, human trials reveal limited bioavailability, with oral squalene poorly absorbed and rapidly metabolized, leading to inconsistent impacts on serum lipid profiles. A review of supplementation studies indicated variable or negligible reductions in total cholesterol, with some evidence of increased endogenous synthesis rather than hypocholesterolemic effects, underscoring the need for higher doses or formulation improvements unattained in clinical settings.^[92]^[93] Industrial applications include exploration as a component in lubricants and polymers, capitalizing on squalene's low viscosity and oxidative stability. In the 2020s, microbial overproduction via engineered yeasts like Pseudozyma sp. has advanced sustainable squalene yields up to optimized fermentation levels, positioning it as a precursor for biofuels in lipid biorefineries that convert microbial oils into renewable diesel alternatives.^[94] This shift supports market growth, with global squalene production projected to incorporate more biosynthetic routes by 2025, reducing reliance on animal sources for high-value chemical feedstocks.^[57]

Safety and Toxicology

General Toxicological Profile

Squalene exhibits low acute oral toxicity in rodent models, with no mortality or adverse effects observed at doses up to 58 g/kg body weight in rats, corresponding to an LD50 exceeding 5 g/kg and classifying it as practically non-toxic under globally harmonized system criteria.^[95] In dermal and inhalation exposure studies, similarly low toxicity profiles are reported, with no systemic effects at high concentrations due to poor absorption through skin or gastrointestinal tract. Repeated-dose and subchronic studies demonstrate a no-observed-adverse-effect level (NOAEL) of approximately 29 g/kg/day in rats over 90 days, with no evidence of organ toxicity, histopathological changes, or altered clinical parameters at tested doses.^[95] Squalene shows no mutagenic potential in bacterial reverse mutation assays or genotoxicity in mammalian cell tests, and it lacks clastogenic activity in vivo micronucleus evaluations; some studies indicate protective effects against oxidative DNA damage induced by xenobiotics. Carcinogenicity data from long-term rodent exposures reveal no tumor promotion or initiation, aligning with OECD guideline-compliant assessments that find no neoplastic risks.^[2] Exogenous squalene is minimally absorbed orally, with fecal excretion predominant, and undergoes hepatic oxidation to hydroxylated and epoxidized derivatives via cytochrome P450 pathways, integrating into cholesterol biosynthesis or elimination routes. Plasma clearance is rapid, with half-lives under 24 hours in pharmacokinetic models, preventing accumulation; its multiple unsaturated bonds facilitate metabolic turnover without persistent tissue retention.^[96] The Cosmetic Ingredient Review Expert Panel deems squalene safe as a cosmetic ingredient at concentrations up to 100% based on use practices and toxicological data.^[97] The U.S. Food and Drug Administration lists it as a permitted indirect food additive and pharmaceutical excipient, reflecting low concern for toxicity in approved applications.^[1]

Human Health Effects and Allergenic Potential

Squalene exhibits high tolerability in human topical and systemic exposures, consistent with its endogenous production as a major sebum component comprising up to 12% of skin surface lipids, where it functions as a natural antioxidant and protectant against environmental oxidants without eliciting adverse reactions.^[2] Clinical assessments, including repeated patch testing on human skin, demonstrate that pure squalene is neither a significant irritant nor contact sensitizer, with adverse dermal responses typically attributable to impurities, oxidation products, or formulation excipients rather than the compound itself. Epidemiological data from cosmetic use and vaccine surveillance underscore rare allergic potential; contact dermatitis incidence remains below 1% in standardized patch tests, often resolving upon purification of squalene sources, and no population-level signals of hypersensitivity have emerged from extensive monitoring. In vaccine contexts, over 30 million doses of AS03-adjuvanted formulations (containing squalene as an emulsion component) were administered during the 2009 H1N1 campaign, with post-marketing analyses of millions of recipients revealing no squalene-attributable systemic toxicity or elevated autoimmune risks beyond background rates.^[98] IgE-mediated allergic responses to squalene are exceptionally uncommon, as its non-protein lipid structure limits immunogenicity and cross-reactivity; isolated reports of hypersensitivity to AS03-adjuvanted vaccines implicate trace contaminants over squalene per se, with negligible overlap to common allergens like latex proteins or olive oil polypeptides, which trigger distinct protein-specific IgE pathways.^[99]^[100] This profile aligns with squalene's biocompatibility, evidenced by its safe incorporation in pharmaceuticals and emollients at concentrations up to 100% without inducing type I hypersensitivity in sensitized cohorts.

Controversies

Vaccine Adjuvant Efficacy and Adverse Event Claims

In the late 1990s and early 2000s, claims emerged linking squalene-containing anthrax vaccines administered to U.S. military personnel during the Gulf War to Gulf War Syndrome (GWS), asserting that squalene induced anti-squalene antibodies (ASA) responsible for chronic symptoms like arthritis and fatigue.^[101] A small pilot study of 19 symptomatic deployed veterans reported ASA in 95% of overtly ill participants, suggesting a potential causal role amplified in subsequent anti-vaccination narratives.^[102] These assertions relied on trace squalene detection in certain vaccine lots, though levels were not intentionally added and occurred at parts-per-billion concentrations insufficient for adjuvant activity. Counter-evidence from larger epidemiological analyses and immunological studies refutes a causal connection between squalene adjuvants and GWS or systemic autoimmunity. The Institute of Medicine's 2002 review of anthrax vaccine safety found no elevated adverse event rates, including local reactions, from the single lot with trace squalene contamination, and subsequent 2012 updates affirmed insufficient evidence linking the vaccine to GWS.^[103] ASA occur naturally at low titers in 39-100% of healthy, unvaccinated adults across cohorts, with prevalence higher in females and unrelated to vaccination history, indicating they do not signify adjuvant-induced pathology.^[104] Vaccines with MF59 (squalene-based adjuvant) do not elevate ASA titers beyond baseline, as confirmed in controlled trials measuring pre- and post-immunization levels.^[104] Large-scale deployments, such as the 2009 H1N1 pandemic response with MF59-adjuvanted vaccines, reported adverse events limited to mild, transient injection-site pain (up to 70%), swelling (4.8%), and myalgia (10.7-42%), resolving without systemic sequelae.^[105]^[106] Empirical data support squalene adjuvants' efficacy in enhancing immune responses, particularly for antigen dose-sparing and immunogenicity in vulnerable populations. Meta-analyses of MF59-adjuvanted influenza vaccines demonstrate superior heterologous strain protection, with the greatest relative benefit in children under 3 years (odds ratio for seroconversion ~4-6 times higher than non-adjuvanted) and sustained gains in elderly adults via improved T-cell and cross-reactive antibody induction.^[107]^[108] These effects enable lower antigen doses while achieving seroprotection rates near 100% after two doses in young children, reducing manufacturing demands during shortages.^[109] Overall benefit-risk profiles remain positive, as adjuvant-enhanced vaccines lower infection rates without causal evidence of severe adverse outcomes beyond localized reactogenicity.^[110]

Sustainability, Shark Harvesting, and Environmental Impacts

Squalene has historically been extracted from the livers of deep-sea sharks, particularly species in the genus Centrophorus such as gulper sharks, which contain high concentrations of the compound for buoyancy.^[111] Harvesting intensified from the 1960s through the 2000s, often as a targeted fishery or byproduct of finning operations, with global demand driving the slaughter of an estimated 3 to 6 million deep-sea sharks annually at peak periods to yield squalene for cosmetics and pharmaceuticals.^[50] This practice has contributed to severe population declines in affected species; for instance, gulper shark stocks in the Maldives dropped by 97% between 1982 and 2002 due to squalene-targeted fishing.^[112] Similarly, multiple Centrophorus species in Australian waters experienced significant reductions from overfishing pressure linked to liver oil extraction.^[113] The International Union for Conservation of Nature (IUCN) classifies many deep-sea squalene-source sharks as vulnerable or endangered, attributing declines to their low reproductive rates, long gestation periods (up to two years), and slow maturity, which limit population recovery.^[114] One-third of endangered deep-sea shark species are specifically targeted for liver oil, with half of those at risk of extinction.^[115] While some shark fisheries impose quotas to manage catches, deep-sea squalene harvesting remains largely unregulated in many regions, exacerbating defaunation; studies indicate overfishing compounded by sensitive life histories has led to irreversible declines in these populations.^[59] Proponents of regulated fisheries argue that quotas in areas like U.S. Atlantic waters demonstrate potential for sustainability in select shark stocks, though such measures rarely extend to deep-sea species due to monitoring challenges and illegal trade.^[116] Market-driven innovation has spurred alternatives to shark-derived squalene, reducing demand through cost-competitive production from microorganisms like Thraustochytrium and Aurantiochytrium species, which yield squalene via fermentation without ecological strain.^[117] Engineered yeasts such as Yarrowia lipolytica enable biosynthesis from waste oils, achieving viable yields as of 2023-2024 studies, while plant sources like olives and amaranth provide lower but scalable options.^[118] These shifts occur voluntarily as biotech costs decline, with global squalene demand increasingly met by non-animal sources, thereby alleviating pressure on shark populations without relying on restrictive regulations.^[119] Environmental impacts extend beyond targeted species to broader marine biodiversity, as habitat disruption from deep-sea trawling for livers contributes to ecosystem imbalances, though shark-derived squalene's role in enabling vaccine adjuvants has supported human health outcomes like enhanced immune responses during pandemics.^[120] Conservation narratives often emphasize extinction risks, yet empirical data on deep-sea shark resilience reveal limited rebound potential due to k-selected life strategies favoring few offspring over rapid reproduction, underscoring the need for evidence-based alternatives over unsubstantiated optimism about natural recovery.^[121] Economic analyses highlight that unsustainable harvesting persists where alternatives lag in purity or volume, but ongoing microbial advancements prioritize innovation to balance biodiversity preservation with industrial utility.^[57]

References

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[PDF] SQUALENE – NATURAL RESOURCES AND APPLICATIONS
Squalene is a natural hydrocarbon (C30H50) with six double bonds, an intermediate for phytosterol/cholesterol, and is found in shark liver oil.Missing: definition | Show results with:definition
[5]
Biosynthesis of Squalene from Farnesyl Diphosphate in Bacteria
Apr 20, 2015 · Squalene (SQ) is an intermediate in the biosynthesis of sterols in eukaryotes and a few bacteria and of hopanoids in bacteria where they ...Supporting Information · Author Information · References
[6]
Increased cholesterol biosynthesis and hypercholesterolemia in ...
Squalene synthase (SS) is the first committed enzyme for cholesterol biosynthesis, located at a branch point in the mevalonate pathway.
[7]
Squalene - the NIST WebBook
Squalene. Formula: C30H50; Molecular weight: 410.7180. IUPAC Standard ... Chemical structure: C30H50 This structure is also available as a 2d Mol file ...
[8]
Squalene - an overview | ScienceDirect Topics
Squalene is a polyunsaturated triterpene containing six isoprene units and is a biochemical precursor of cholesterol and other steroids. Squalene is commonly ...
[9]
Squalene | C30H50 - ChemSpider
Squalene has the molecular formula C30H50 and an average mass of 410.730. It is also known as (6E,10E,14E,18E)-2,6,10,15,19,23-Hexamethyl-2,6,10,14,18,22- ...
[10]
One of the linkages in squalene is tail-to-tail, not head-to-tail. What d..
Jun 1, 2024 · Final Answer: The tail-to-tail linkage in squalene suggests that it is synthesized by the condensation of two farnesyl diphosphate molecules in ...
[11]
Recombinant squalene synthase. Synthesis of non-head-to-tail ...
Two of the major products, (Z)-dehydrosqualene (DSQ) and (R)-12-hydroxysqualene (HSQ), have the same 1'-1 linkage between the farnesyl units from FPP that is ...
[12]
The mammalian cholesterol synthesis enzyme squalene ...
Squalene monooxygenase (SM, also known as squalene epoxidase) is a rate-limiting enzyme of cholesterol synthesis that converts squalene to monooxidosqualene ...
[13]
A key mammalian cholesterol synthesis enzyme, squalene ... - PNAS
Mar 13, 2020 · Squalene monooxygenase (SM) is a rate-limiting enzyme in the cholesterol biosynthetic pathway and has been demonstrated to be posttranslationally regulated.
[14]
The shape of human squalene epoxidase expands the arsenal ...
Feb 21, 2019 · Squalene epoxidase (also known as squalene monooxygenase, EC 1.14.99.7) is a key rate-limiting enzyme in cholesterol biosynthesis.
[15]
111-02-4(Squalene) Product Description - ChemicalBook
Melting point: −75 °C(lit.) Boiling point: 285 °C25 mm Hg(lit.) Density, 0.858 g/mL at 25 °C(lit.) vapor pressure, 0Pa at 25℃.Missing: physical | Show results with:physical
[16]
Oxidation of squalene by singlet oxygen and free radicals results in ...
Jun 14, 2018 · During singlet oxygen oxidation, singlet oxygen acts as an electrophilic reagent that reacts with double bonds via the ene reaction to form ...
[17]
Reactions and Products of Squalene and Ozone: A Review - PMC
Squalene, a component of human skin oil, contains six carbon–carbon double bonds and is very reactive with ozone. Bioeffluents from people contribute to indoor ...3. The Sqoz Reaction · 4. Sqoz Reaction Kinetics · 6.2. Toxicity And Health...
[18]
Chemical Properties of Squalene (CAS 111-02-4) - Cheméo
Squalene's formula is C30H50, molecular weight is 410.72, CAS is 111-02-4, and boiling point is 910.04 K.
[19]
1H NMR combined with PLS for the rapid determination of squalene ...
Jul 30, 2019 · With NMR spectroscopy, complete information about the molecular composition of fatty acids, squalene, sterols, triterpene acids/esters, fatty ...
[20]
Ion-trap tandem mass spectrometric analysis of squalene ...
We prepared pure SQ-OOH isomers and developed an analytical method for SQ-OOH isomers using a quadrupole/linear ion-trap mass spectrometer (QTRAP) MS/MS system.
[21]
Expression analysis of squalene synthase gene in mevalonate ...
Apr 10, 2022 · Squalene synthase (SQS) is a key enzyme in the MVA pathway, which is responsible for condensing two molecules of farnesyl diphosphate (FPP) into ...
[22]
Squalene Synthase - an overview | ScienceDirect Topics
Squalene synthase is a late step in cholesterol biosynthesis. The effect on LDL is similar to the HMG-CoA reductase inhibitors, with decreased cholesterol ...<|separator|>
[23]
27.7: Biosynthesis of Steroids - Chemistry LibreTexts
Sep 30, 2024 · Lanosterol biosynthesis begins with the selective epoxidation of squalene to give (3S)-2,3-oxidosqualene, catalyzed by squalene epoxidase.
[24]
Biosynthesis of Cholesterol and Other Sterols - PMC - PubMed Central
The cyclization of squalene-2,3-oxide (1) catalyzed by the lanosterol synthase (LAS) or cycloartenol synthase (CAS) to give true sterols. Ring annulation ...
[25]
Squalene 2,3-epoxide cyclizes, forming lanosterol - Reactome
Lanosterol synthase (LSS) catalyzes the cyclization of squalene 2,3-epoxide to lanosterol, a reaction that forms the sterol nucleus.Missing: synthesis | Show results with:synthesis
[26]
Cholesterol-Dependent Degradation of Squalene Monooxygenase ...
Mar 2, 2011 · Exquisite control of cholesterol synthesis is crucial for maintaining homeostasis of this vital yet potentially toxic lipid. Squalene ...
[27]
Feedback Regulation of Cholesterol Synthesis: Sterol-Accelerated ...
Sterols trigger HMG CoA reductase binding to Insigs, leading to ubiquitination and degradation, which controls cholesterol synthesis.
[28]
Sterol homeostasis requires regulated degradation of squalene ...
Sterol homeostasis is essential for the function of cellular membranes and requires feedback inhibition of HMGR, a rate-limiting enzyme of the mevalonate ...
[29]
Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular ...
Jun 14, 2018 · ... Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway. ... The mevalonate pathway regulates primitive streak ...
[30]
Lipid, fatty acid and squalene composition of liver oil from six ...
All sharks had different lipid compositions, but similar fatty acid and diol profiles. The high squalene content (50–82% of oil) of all species, except ...
[31]
Recent Progress in Microalgal Squalene Production and ... - PubMed
Jun 29, 2022 · In the human body, a significant excretion named as sebum includes squalene in 12 percent. This bioactive compound shows anti-inflammatory ...
[32]
Techno-economic evaluation of squalene recovery from oil ...
The squalene concentration in vegetable oils varies between 9.9 mg/100 g for soybean oil and 564 mg/100 g for olive oil (Popa et al., 2015). However, the ...Missing: percentages | Show results with:percentages
[33]
Anti-Inflammatory and Antioxidant Properties of Squalene in Copper ...
May 10, 2023 · The DPPH assay demonstrated that the highest free radical scavenging exerted by squalene was 32%. The fluorescence intensity of reactive oxygen ...
[34]
The physiological function of squalene and its application prospects ...
Jan 16, 2024 · Interestingly, all six double bonds are trans structures. As a result, SQ is less stable, oxidizes easily, and gives off a peculiar fishy smell ...
[35]
Squalene targets pro- and anti-inflammatory mediators and ...
In fact, squalene is a highly effective antioxidant acting as a direct reactive oxygen species (ROS) scavenging agent reducing intracellular oxidant stress ...
[36]
Kinetics of Squalene Quenching Singlet Oxygen and the Thermal ...
Jul 2, 2024 · Different degradation kinetic models; retention index of products 1–6; free radical scavenging activities determined with DPPH, ORAC, ABTS ...
[37]
Vascular effects and safety of supplementation with shark liver oil in ...
Jun 11, 2015 · Shark liver oil (SLO) has long been used as a traditional health food, with a particular benefit for vascular health, in Japan.
[38]
70 years of squalane history: Why is olive squalane taking the lead?
Squalene was also discovered by a Japanese Mitsumaru Tsujimoto in 1906 in shark liver oil. Japan is a fishing country. Squalane has perfect properties for ...
[39]
Methods for Obtaining and Determination of Squalene from Natural ...
Squalene was discovered in 1906 by the Japanese researcher Dr. Mitsumaru Tsujimoto, an expert in oils and fats at Tokyo Industrial Testing Station. He separated ...
[40]
Experiments with the Unsaturated Hydrocarbon, Squalene ...
The Biological Significance of the Unsaponifiable Matter of Oils: Experiments with the Unsaturated Hydrocarbon, Squalene (Spinacene). Biochem J. 1926 ...Missing: structure | Show results with:structure
[41]
The effect of the administration of squalene and other hydrocarbons ...
The effect of the administration of squalene and other hydrocarbons on cholesterol metabolism in the rat · Harold John Channon · George Roland Tristram.Missing: structure | Show results with:structure
[42]
The Biosynthetic Pathway for Cholesterol: Konrad Bloch
Mar 11, 2005 · The elucidation of the pathway from acetic acid to cholesterol was not only a tremendous achievement for biochemistry but also of great ...
[43]
[PDF] Konrad Bloch - The biological synthesis of cholesterol - Nobel Prize
in a biosynthetic pathway that leads to squalene and to sterol, as it does in yeast and liver. In bacteria, sterol synthesis does not occur, but since ...
[44]
COSMETICS INDUSTRY DRIVES DEEP-SEA SHARK EXTINCTIONS
Nov 22, 2012 · Squalane can also be extracted from plants, especially olives. BLOOM's study estimates that around 90% of the world shark liver oil production ...
[45]
“World in motion” – emulsion adjuvants rising to meet the pandemic ...
Dec 21, 2021 · MF59 is an oil-in-water emulsion adjuvant that was first approved in Europe in 1997, in an improved influenza vaccine for adults aged 65 years ...
[46]
The history of MF59(®) adjuvant: a phoenix that arose from the ashes
The first clinical trial of an MF59(®)-adjuvanted influenza vaccine (Novartis) was conducted 20 years ago in 1992.
[47]
Metabolic Engineering for Squalene Production: Advances and ...
Dec 3, 2024 · lipolytica has demonstrated the capability to produce significant amounts of squalene, achieving squalene concentrations of 32.8 g/L and 51.2 g/ ...
[48]
Enhancing Squalene Production in Saccharomyces cerevisiae by ...
Jan 18, 2022 · The production of squalene was enhanced by 18.4%, permitting 8.2 g/L of squalene to be produced by a two-stage fermentation strategy, in a 5-L ...
[49]
Metabolic engineering of Saccharomyces cerevisiae for squalene ...
The engineered strain produced 22.4 g/L squalene from lignocellulosic hydrolysates. Abstract. Bio-refining lignocellulosic resource is an economically feasible ...
[50]
Microbial genetic engineering approach to replace shark livering for ...
Squalene typically accounts for 40–60% of the shark liver mass. In sharks such as Centrophorus moluccensis (smallfin gulper shark), almost 83% of the liver mass ...
[51]
Fatty acid and squalene compositions of Mediterranean ... - PubMed
The relative weight of the liver ranges from 15 to 29% of total body weight; 63 to 89% of the liver weight is oil. Squalene, the major component (49-89% in oil) ...<|separator|>
[52]
From Sharks to Yeasts: Squalene in the Development of Vaccine ...
Extracting squalene from shark liver oil implicates lower financial costs and it is a fairly simple process: a single distillation under vacuum at 200–300 °C is ...
[53]
Microbial Squalene: A Sustainable Alternative for the Cosmetics and ...
Aug 27, 2024 · Pseudozyma sp. produces over 2 g/L squalene without having to undergo any strain engineering [36]. Candida famata [13], Rhodopseudomonas ...1 Introduction · 6.1 Yarrowia Lipolytica · 7.1 Saccharomyces Cerevisiae
[54]
Plant Sources, Extraction Methods, and Uses of Squalene - 2018
Aug 1, 2018 · The SQ extracted from shark liver oil is the most appreciated for its high yield (up to 40% of the weight of the organ); however, the ...
[55]
Squalene and Sharks – Shark Stewards
Squalene (or squalane is when it is processed for products) is a natural oil that comes from shark liver. The molecule C30H50 is also found in many plants such ...
[56]
[PDF] Shark in our beauty creams - BLOOM Association
Apr 21, 2018 · The annual demand for squalene is between 1,000-2,000 tons, and the number of sharks required to make one ton of squalene is approximately 3, ...Missing: historical peaks
[57]
Microbial Squalene: A Sustainable Alternative for the Cosmetics and ...
Aug 30, 2024 · According to estimates, approximately 3000 sharks must be killed to produce 1 ton of squalene. ... Production of Squalene,” World Journal of ...Missing: historical peaks
[58]
Fishing for deep sea shark data
Jul 9, 2025 · If sharks are retained onboard, it is usually for squalene, the oil contained in their livers used in cosmetics and skin care products. FAO is ...
[59]
Fishing for oil and meat drives irreversible defaunation of deepwater ...
Mar 7, 2024 · We show that deepwater sharks and rays have experienced population decline due to overfishing compounded by highly sensitive life histories ...Missing: harvesting | Show results with:harvesting
[60]
[PDF] FAO Fisheries and Aquaculture Report No. 897 FIMF/R897 (En)
This report documents the discussions and conclusions of the Technical Workshop that was held to evaluate the current limitations in the monitoring of shark ...<|separator|>
[61]
Engineering Strategies in Microorganisms for the Enhanced ...
Mar 22, 2019 · Prokaryotes such as bacteria and cyanobacteria possess the MEP pathway whereas eukaryotes comprising yeast, higher fungi, plants, animals and ...
[62]
Using Engineered Escherichia coli to Synthesize Squalene ... - bioRxiv
Oct 29, 2020 · Human squalene synthase (hSQS) efficiently catalyzes the synthesis of squalene. Also, mevalonate (MVA) pathway would increase the yield of the ...
[63]
Genetic and bioprocess engineering to improve squalene ...
HMG-CoA reductase (HMG1) is the first rate-limiting enzyme in the mevalonate pathway and plays critical role in regulating squalene biosynthesis (Ma et al., ...
[64]
Improving squalene production by enhancing the NADPH/NADP + ...
Mar 28, 2019 · A fivefold squalene titer increase was achieved by expressing rate-limiting enzymes (IDI, DXS, and FPS) involved in the isoprenoid pathway.
[65]
Recent advances in the microbial production of squalene - PMC
Apr 15, 2022 · Considerable progress has been made using both wild-type and engineered microbial strains for improved productivity and yields of squalene.
[66]
Engineering peroxisomal biosynthetic pathways for maximization of ...
Jan 23, 2024 · (B) Engineering lipid biosynthesis and hydrolysis by overexpressing rate-limiting enzymes increased squalene production in the peroxisome.
[67]
Efficient synthesis of squalene by cytoplasmic-peroxisomal ...
Finally, the squalene production reached 51.2 g/L by fed-batch fermentation in a 5-L bioreactor. This is the highest squalene production reported to date for ...
[68]
Production of squalene and fatty acids by Thraustochytrium sp ...
Sep 16, 2025 · HX-308 was shown to provide a squalene titer of 13.73 g L−1 (Table 3) in a fed-batch that had a dry biomass concentration of 96 g L−1 (Xu et al.
[69]
Co-production of DHA and squalene by thraustochytrid from forest ...
Feb 6, 2020 · The present study sought to optimize DHA and squalene production by the thraustochytrid Schizochytrium limacinum SR21.Missing: titers | Show results with:titers
[70]
Amyris starts squalene production at plant in Brazil
Aug 1, 2022 · Amyris said it had developed a process to produce sugarcane-derived squalene as an alternative to non-sustainable shark-derived squalene. Amyris ...
[71]
AMYRIS BARRA BONITA FERMENTATION PLANT BEGINS ...
Jun 23, 2022 · The plant's capacity is fully committed through the end of 2023 with the production of natural vanillin, sugarcane-based Reb M, squalane, ...
[72]
From Olive Pomace to Squalane: A Green Chemistry Route Using 2 ...
Jul 25, 2025 · This study highlights 2-MeTHF's potential for industrial-scale SQE valorization via integrated extraction and hydrogenation. Future efforts ...
[73]
Squalene Market Size, Industry Share Forecast & Trends Report
Sep 17, 2025 · The global squalene market size was valued at USD 141 million in 2022 and is projected to reach USD 202 million by 2028, growing at 6.3% ...Missing: milestones | Show results with:milestones<|control11|><|separator|>
[74]
The Formulator's Guide to Squalene and Squalane - Formula Botanica
By saturating the six double bonds found in squalene, squalane becomes a stable, non-oxidising compound. Unlike squalene, squalane does not possess ...
[75]
What Is Squalane and What Are Its Benefits for Skin and Hair?
Squalane is a natural antioxidant that mimics skin oils, hydrating skin and hair, and may reduce inflammation and damage. It is made from hydrogenated squalene.
[76]
https://beminimalist.co/blogs/skin-care/squalane-vs-squalene-for-skin-the-subtle-yet-profound-difference
[77]
Retinol in Squalane - Skin Biology
In stock Rating 5.0 (2) Retinol in Squalane quickly penetrates the skin and adds vital Vitamin A to nourish dry skin areas.
[78]
https://www.biossance.com/c/shop-by-skin-concern/squalane-skincare-for-antiaging/
[79]
Immunology and efficacy of MF59-adjuvanted vaccines - PMC - NIH
A MF59-adjuvanted seasonal influenza vaccine (Fluad®) was first licensed in 1997 for the elderly, and since then have been approved to be included in human ...
[80]
Development and evaluation of AS03, an Adjuvant ... - PubMed
By incorporating AS03 in the pandemic H1N1/2009 vaccine, vaccine immunogenicity was increased compared with nonadjuvanted H1N1 vaccines. High H1N1/2009/AS03 ...
[81]
An alternative renewable source of squalene for use in emulsion ...
MF59® is a submicron oil-in-water emulsion containing Span85, Tween80 and squalene as the oil phase. Fluad® (MF59® adjuvanted seasonal flu vaccine) has been an ...
[82]
The adjuvant MF59 induces ATP release from muscle that ... - PNAS
Here we show that ATP release from muscle is crucial for the mechanism of action of the vaccine adjuvant MF59, leading to efficient CD4 T-cell priming and high ...
[83]
The Mechanism of Action of MF59 - An Innately Attractive Adjuvant ...
Jun 19, 2012 · Here we present a summary of all the work performed to date on the mechanism of action of MF59 and we present a unified theory based on the ...
[84]
The adjuvant MF59 increases the immunogenicity and protective ...
Influenza vaccine combined with MF59 gave full protection from viral challenge at antigen doses 65- to 80-fold lower than with vaccine alone.Missing: flu | Show results with:flu
[85]
Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine ...
Jul 21, 2015 · The AS03 adjuvant contained 10.68 mg squalene per administered dose and the MF59 adjuvant contained 9.75 mg squalene per administered dose.
[86]
Squalene emulsion-based vaccine adjuvants stimulate CD8 T cell ...
Many adjuvants can induce activation of the innate immune system, which programs the magnitude, quality and durability of the adaptive immune response ...
[87]
Biophysical characterization of asolectin-squalene liposomes
Oct 1, 2018 · Liposomes are shell nanoparticles able to embed hydrophobic molecules into their lipid layers to be released to cells. In pharmaceutical ...
[88]
Conjugation of squalene to gemcitabine as unique approach ...
May 30, 2017 · Here we show that nanoparticles made of the squalene derivative of gemcitabine (SQGem) interact with lipoproteins (LPs), indirectly enabling the targeting of ...
[89]
Lipid nanoparticles for RNA delivery: Self-assembling vs driven ...
Squalene is a natural cholesterol precursor which is gaining a growing attention as a pharmaceutical excipient in drug delivery systems, due to its high ...
[90]
Squalene in Nanoparticles Improves Antiproliferative Effect on ...
Squalene, a triterpene found in extra virgin olive oil, has therapeutic properties in diseases related to oxidative stress, such as cancer.
[91]
Squalene Epoxidase: Its Regulations and Links with Cancers - PMC
In recent years, more and more studies have shown that SQLE is elevated in cancers and the dysregulation of SQLE could result in cholesterol metabolism disorder ...
[92]
Interdependence of Anti-Inflammatory and Antioxidant Properties of ...
This study may indicate that SQ supplementation can increase cholesterol synthesis with an inconsistent pattern. Therefore, these human studies have shown an ...Missing: bioavailability | Show results with:bioavailability
[93]
Squalene: More than a Step toward Sterols - PMC - PubMed Central
Aug 2, 2020 · Squalene (SQ) is a natural triterpene widely distributed in nature. It is a metabolic intermediate of the sterol biosynthetic pathway.
[94]
Optimization of Squalene Production by Pseudozyma sp. P4-22 - PMC
Apr 7, 2025 · Under optimal cultivation conditions, the biomass and squalene production reached 64.42 g/L and 2.06 g/L, respectively, in a 5 L fed-batch ...
[95]
Squalene: A Trove of Metabolic Actions - IntechOpen
Oct 26, 2016 · Squalene, found in olive oil, is an oxygen-scavenging agent that decreases hepatic lipids by promoting VLDL output and fatty acid oxidation.
[96]
(PDF) Measurement of squalene in human tissues and plasma
Sep 20, 2025 · ... half-lives of metabolically "active" squalene also were obtained. This measurement of daily cholesterol synthesis by squalene kinetics ...
[97]
[PDF] Squalane and Squalene - Cosmetic Ingredient Review |
Jun 1, 2018 · 1 The Panel concluded that “both Squalane and Squalene are safe as cosmetic ingredients in the present practices of use and concentration,” as ...
[98]
Safety of AS03-adjuvanted influenza vaccines: A review of the ...
May 21, 2019 · AS03-adjuvanted influenza vaccines were generally well tolerated and displayed an acceptable safety profile, although the power to detect rare events was ...
[99]
Vaccine-associated hypersensitivity - PMC - NIH
The importance of distinguishing acute-onset IgE-mediated reactions is that they can manifest as severe life-threatening anaphylaxis in the patient and require ...
[100]
[PDF] Allergic reactions after vaccination: translating guidelines into ...
Cases of suspected IgE-mediated reactions have been documented in H1N1 influenza vaccines due to squalene adjuvant AS03 (32). Residual contaminants (of the ...
[101]
Antibodies to squalene in Gulf War syndrome - PubMed
Serum antibodies to squalene were measured. In our small cohort, the substantial majority (95%) of overtly ill deployed GWS patients had antibodies to squalene.
[102]
Antibodies to Squalene in Gulf War Syndrome - ScienceDirect
Serum antibodies to squalene were measured. In our small cohort, the substantial majority (95%) of overtly ill deployed GWS patients had antibodies to squalene.
[103]
6 Safety: Epidemiologic Studies | The Anthrax Vaccine: Is It Safe ...
Receipt of vaccine from the one lot that was found to have traces of squalene contamination did not produce an elevated rate of local reactions (5.3 percent of ...
[104]
Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody ...
In conclusion, antisqualene antibodies are not increased by immunization with vaccines with the MF59 adjuvant. These data extend the safety profile of the MF59 ...
[105]
Trial of 2009 Influenza A (H1N1) Monovalent MF59-Adjuvanted ...
MF59, a proprietary oil-in-water–emulsion adjuvant, was first licensed for use in seasonal influenza vaccines in 1997. Over 40 million doses have been ...
[106]
Comparison of the adverse events associated with MF59 ... - PubMed
The most frequent adverse events were swelling at the injection site and myalgia, which were noted in 4.8% and 10.7% of participants, respectively.
[107]
Association between vaccine adjuvant effect and pre-seasonal ...
Dec 24, 2019 · This meta-analysis indicates the highest benefit of squalene-IIV over aqueous IIV in young children and decreasing benefit with progressing age.Missing: efficacy studies
[108]
Squalene-Based Influenza Vaccine Adjuvants and Their Impact on ...
Mar 17, 2021 · Squalene-based emulsion adjuvants induce a strong innate immune response, enhancing antigen presentation both quantitively and qualitatively to generate strong ...
[109]
Assessment of squalene adjuvanted and non-adjuvanted vaccines ...
Solicited systemic reactions were fever, headache, malaise, myalgia and shivering for subjects aged at least 24 mo, and fever, vomiting, abnormal crying, ...
[110]
Oil-in-water emulsion adjuvants for pediatric influenza vaccines
Jan 16, 2020 · These results indicate that oil-in-water emulsion adjuvant improves the efficacy of inactivated influenza vaccines in healthy young children.
[111]
Fishing for Squalene - Shark Allies
Jun 21, 2025 · In other words, their populations are more likely to be easily decimated if sexually mature sharks with the largest livers are the ones being ...
[112]
National poll shows Maldivians oppose shark fishery reopening
Oct 8, 2025 · A 2024 report found that the population of gulper sharks in Maldives waters fell by 97 per cent between 1982 and 2002, with the fishery ...
[113]
[PDF] NOTIFICATION TO THE PARTIES - CITES
Nov 8, 2024 · Several species of gulper sharks have undergone significant declines in Australia as a result of fishing pressure. This was primarily due to ...<|separator|>
[114]
Everything You Need To Know About Shark Squalene - ReefCause
Jul 5, 2021 · Deep-sea Sharks Are Particularly Vulnerable To Extinction ... Many of these shark species are listed as vulnerable on the IUCN Red List of ...
[115]
Shark Liver Oil Study - AZA.org
Mar 31, 2024 · “One-third of the endangered species in this group are specifically hunted, and half of those targeted for liver oil are at risk of extinction,” ...
[116]
How Retention Limits Help Us Sustainably Manage Shark Fisheries
Oct 9, 2019 · Annual shark quotas are the maximum amount of a species or species group that can be taken from the ocean each year by all fishermen combined.Missing: squalene | Show results with:squalene<|separator|>
[117]
Sustainable Alternatives for Squalene Production - PMC - NIH
Mar 19, 2025 · This study investigated a sustainable alternative to squalene production utilizing Thraustochytrium sp. and Aurantiochytrium sp., thereby reducing dependence ...Missing: titers | Show results with:titers
[118]
Sustainable biosynthesis of squalene from waste cooking oil by the ...
Aug 6, 2025 · In this study, we applied metabolic engineering principles to enhance squalene production in the nonconventional yeast Y. lipolytica, using ...Missing: algae | Show results with:algae<|separator|>
[119]
Gulper sharks: Maldives risks reputational damage - Divernet
Sep 24, 2025 · “Global demand for shark-derived squalene is declining as cheaper, plant-based alternatives – derived from olives, sugarcane and amaranth seeds ...
[120]
Why a COVID-19 vaccine could further imperil deep-sea sharks
Nov 13, 2020 · It takes the livers of between 2,500 and 3,000 sharks to extract about a ton of squalene. Conservationists fear that increased demand for ...Missing: resilience | Show results with:resilience<|control11|><|separator|>
[121]
Supporting the Sustainable Management of Gulper Sharks
Apr 2, 2025 · These population declines are the direct result of overfishing driven by the demand for their liver oil that is traded internationally.