Squalene

Squalene: A Comprehensive Reference

1. Identity and Chemical Characterization

Chemical Names and Identifiers

Squalene is a natural dehydrotriterpenic hydrocarbon (C₃₀H₅₀) with six double bonds, known as an intermediate in the biosynthesis of phytosterol or cholesterol in plants or animals. Its IUPAC systematic name is 2,6,10,15,19,23-hexamethyl-2,6,10,14,18,22-tetracosahexaene, and it is registered under CAS number 7683-64-9. In 1916, Tsujimoto Mitsumaru, a Japanese chemist, successfully isolated squalene (C₃₀H₅₀) from shark liver oil (Squalus spp.) and found that the compound was a highly unsaturated isoprenoid hydrocarbon containing six double bonds.

Squalene (with an "e") is the natural, unsaturated form. Because it oxidises rapidly when exposed to air, it cannot be used directly in skincare products. Through a process called hydrogenation, squalene is converted into squalane (with an "a") — a saturated, stable form that retains the moisturising and emollient properties without the risk of going rancid.

Natural Sources and Distribution

Squalene is a natural lipid belonging to the terpenoid family and a precursor of cholesterol biosynthesis. It is synthesized in humans and also in a wide array of organisms and substances, from sharks to olives and even bran, among others.

Animal sources: The largest squalene natural source is the liver oil of certain fish, especially deep-sea sharks, from which it derives its name (Squalus spp.). In the case of deep-sea sharks, the liver is the main organ for lipids' storage, being at the same time an energy source and means for adjusting buoyancy. In their case, the unsaponifiable matter represents 50–80% of the liver, the great majority thereof being squalene. More specifically, the main traditional source of squalene is shark liver oil, with a concentration reaching 40–86 g per 100 g.

Human endogenous production: Human sebum also contains 13% squalene as one of its major constituents. It is transported in serum generally in association with very low-density lipoproteins and is distributed ubiquitously in human tissues, with the greatest concentration in the skin.

Plant sources: Squalene is widely distributed in nature, with reasonable amounts found in olive oil, palm oil, wheat-germ oil, amaranth oil, and rice bran oil. Quantitatively, olive oil (486 mg/100 g oil) and amaranth oil (9.87 g/100 g oil) have the highest levels of squalene, with lesser quantities found also in soybean oil (9.9 mg/100 g), grape seed oil (14.1 mg/100 g), palm oil (20–50 mg/100 g), wheat germ oil, peanut oil (27.4 mg/100 g), and rice bran oil (320 mg/100 g). Additional plant sources include rice bran, palm oil, Brazil nut, avocado, sunflower seed, borage, soybean, peanut, macadamia, pistachio, almond, and walnut.

Market supply: Nowadays, olive oil-derived squalene represents 55% of the global market, which is still insufficient to completely replace shark-derived squalene. Because sharks are the primary source of squalene, there is a need to identify low-cost, environment-friendly, and sustainable alternatives for producing squalene commercially. This shift has prompted scientists to apply biotechnological advances to research microorganisms for synthesizing squalene.

Common Forms and Preparations

Squalene is a polyunsaturated hydrocarbon with a formula of C₃₀H₅₀. Squalene can be found in certain fish oils, especially shark liver oil, in high amounts and some vegetable oils in relatively smaller amounts. As a dietary supplement, it is most commonly marketed in softgel capsule form derived from shark liver oil. Squalene is known for use in oil-in-water emulsions in human vaccines, for instance the MF59 emulsion that is used for adjuvanting influenza vaccines. Squalene is also used in other pharmaceutical products (e.g., ointments, suppositories) and in cosmetics. It is also used as a material in topically applied vehicles such as lipid emulsions and nanostructured lipid carriers (NLCs).

2. Historical and Traditional Use

East Asian Traditions

From ancient times, fishermen all over the world benefited from the wonderful properties of the oil extracted from the liver of sharks living beneath 1,000 m. The shoguns from ancient Japan recognized the benefits of the deep-sea sharks liver oil, as a source of power, force, energy, and vitality, calling it "Tokubetsu no Miyage," meaning "precious gift." This oil was also known and used by coastal residents and fishermen in Micronesia, who referred to it as "miraculous oil." Locals from the Japanese peninsula Izu called this shark liver oil "Samedawa," meaning "cure-all," and used it to cure a wide range of conditions.

Scientific Discovery and Early Characterization

Interest in squalene was raised after its characterization in shark liver oil, which is used as a traditional medicine for decades. The compound was first described by the Japanese chemist Tsujimoto in 1906, who identified an unusual oil in shark liver. He later in 1916 used fractional vacuum distillation on liver oil of various species of deep-sea sharks, finding its formula was actually C₃₀H₅₀. It was especially concentrated in liver oil of the Squalidae, leading to the name squalene. In 1931, Karrer and Helfenstein synthesized squalene from farnesyl bromide, thus determining its structure.

Wartime and Modern Supplemental Use

Historically, shark liver has been used for vitamin A, particularly during World War II when the east coast cod fishery was blockaded and shut down. Following the postwar period, shark liver oil began to be used broadly as a dietary supplement, with squalene being recognized as the primary bioactive component. The other major traditional natural source for squalene, olive oil, brought into the attention of the scientific community the healthy properties of an olive oil-based diet.

3. Key Constituents, Biochemistry, and Mechanisms of Action

Role in Cholesterol Biosynthesis

Squalene is a biochemical precursor to both steroids and hopanoids. For sterols, the squalene conversion begins with oxidation (via squalene monooxygenase) of one of its terminal double bonds, resulting in 2,3-oxidosqualene. The endogenous synthesis of squalene begins with the production of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). The initial reduction of HMG CoA (a niacin-dependent reaction) results in the formation of mevalonate.

Squalene, an intermediate for cholesterol biosynthesis, has been proposed to act similarly to statins via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the liver. This feedback inhibition is proposed as a mechanism by which exogenously administered squalene may paradoxically help regulate cholesterol levels despite being a cholesterol precursor.

Antioxidant Mechanisms

Growing interest has been focused on squalene's antioxidant properties, derived from its chemical structure. Strong evidence provided by ex vivo models underlines its scavenging activity towards free radicals, whereas only a few studies have highlighted its effect in cellular models of oxidative stress. The presence of this double bond structure enabled the isoprenoid hydrocarbon to act as a strong antioxidant and natural antibiotic.

An in vitro study has reported that the rate constant of quenching of singlet oxygen by squalene, the first target lipid in human skin surface by various oxidative damage, is much higher than other skin surface lipids in humans and is even comparable to that of 3,5-di-t-butyl-4-hydroxytoluene, an effective lipophilic antioxidant.

Anticancer Mechanisms

The suggested mechanism by which squalene could inhibit tumor formation implies either its inhibitory effect on the catalytic activity of β-hydroxy-β-methylglutaryl-CoA (HMG CoA) reductase and subsequent inhibition of farnesylation of Ras oncoproteins, or modulation of the biosynthesis and of the functional activity of the enzymes involved in xenobiotic metabolism, or its action as a free radical scavenger.

Ferroptosis and Cell Survival

Squalene synthase is a key enzyme that not only participates in the mevalonate pathway, resulting in cholesterol, but also acts as a potential ferroptosis regulator. The synthesis of squalene and its release in the endoplasmic reticulum protects the cell against lipid peroxidation, resulting in cell survival.

Immune System Modulation

Squalene enhances the immune response to various associated antigens, and it is therefore being investigated for vaccine delivery applications. MF59 — a squalene-based vaccine adjuvant — enhances immune responses to antigen by targeting three different cell types, including monocytes, macrophages, and granulocytes. MF59 has a range of effects on these cells, including increased antigen uptake, release of chemoattractants, and induction of cell differentiation.

Absorption and Pharmacokinetics

In mammals, around 60 to 85% of an orally administered squalene, similar to cholesterol, is absorbed through lymphatic vessels of the gastrointestinal tract and then transported in the blood by the very low-density lipoproteins and low-density lipoproteins to the various target organs and tissues where it exerts in vivo biological function. Toxicological studies show that squalene is well tolerated when consumed orally and that it has a faster time of absorbance when compared to cholesterol.

Since this triterpene is well absorbed orally, it has been used to improve the oral delivery of therapeutic molecules.

4. Scientific Evidence by Area of Use

4a. Cardiovascular Disease and Lipid Modulation

Squalene (SQ), an unsaturated hydrocarbon naturally synthesized in plants and animals, has been proposed as an alternative treatment or supplementary agent for cardiovascular health. SQ has been shown to exert cardioprotective effect via its antioxidant activity.

Systematic review evidence (2020): A systematic review of the literature was performed to identify relevant studies about squalene and cardiovascular disease (CVD). A comprehensive search in Medline and Scopus for relevant studies published between the years 1946 and 2019 was performed. The literature searches identified 5,562 potentially relevant articles, whereby 21 studies met the inclusion criteria. There were three human studies and 18 animal experimental studies included in this paper. Only one human study reported a positive outcome of squalene in CVD. The remaining two studies reported inconsistent and/or no effect. For animal studies, 15 studies reported a positive effect while the remaining reported negative and/or no effect of squalene on various related parameters. This evidence-based review emphasizes the potential of squalene being used for cardiovascular-related diseases. The effect of squalene, especially of plant-based squalene, warrants further exploration. Controlled human observational studies should be performed to provide comprehensive evidence.

Animal evidence: Supplementation of squalene extracted from shark liver oil to isoprenaline-MI induced rats for 45 days demonstrated a significant decrease in total cholesterol and triglycerides in comparison to the control group. Khor and Chieng (1997) fed a semisynthetic diet with 20% fat in palm oil triacylglycerol (POTG) to hamsters supplemented with 0.1% squalene for 45 days. There was a significant reduction of serum total cholesterol level and significant increase in liver total lipids and total cholesterol contents when compared to the POTG-control group. In a study conducted by Shin et al. (2004), comparison between plant squalene (from amaranth grain) and animal squalene (from shark liver oil) revealed that amaranth squalene had caused a significant decrease in serum and liver lipids when compared to those of control and shark squalene-treated groups.

Human evidence (vascular function): The effect of eight weeks of dietary supplementation with 1,500 mg shark liver oil (containing 582 mg as squalene) daily was compared with that of placebo on indices of central arterial stiffness and peripheral microvascular function. Supplementation with shark liver oil and thus squalene did not show clinically significant effects on weight, blood pressure and heart rate, or on serum levels of lipids, glucose or any other laboratory test parameters. One of the main findings was the presence of a correlation between squalene supplementation-induced changes in arterial stiffness and age; lower ages were associated with greater decreases in arterial stiffness after the eight-week supplementation period. No difference, however, was found in the mean changes of arterial stiffness between the placebo and SLO groups.

Evidence strength: Predominantly animal and in vitro data. Human trial evidence is limited to a small number of studies, with mixed results. The 2020 systematic review identified only three human studies, only one of which showed a positive outcome. Robust controlled human trials are lacking.

4b. Antioxidant Activity and Oxidative Stress

Squalene is involved in the biosynthesis of phytosterol, cholesterol, and vitamin D; it protects human skin from UV radiation and other oxidative effects, regulates the cardiovascular system, has the ability to capture free radicals and bind toxic compounds and carcinogens.

Growing interest has been focused on squalene's antioxidant properties, derived from its chemical structure. Strong evidence provided by ex vivo models underlines its scavenging activity towards free radicals, whereas only a few studies have highlighted its effect in cellular models of oxidative stress. Given the role of unbalanced free radicals in both the onset and progression of several cardiovascular diseases, an in-depth evaluation of squalene's contribution to antioxidant defense mechanisms could represent a strategic approach in dealing with these pathological conditions.

In a cell culture experiment, squalene-induced protection against cisplatin and carboplatin-induced toxicity in mesenchymal stem cells was shown to be directly associated with the decreased reactive oxygen species production and improved cellular glutathione homeostasis.

Evidence strength: Ex vivo and in vitro evidence is moderately strong for free radical scavenging. Evidence from human clinical studies specifically testing squalene's antioxidant capacity as a primary endpoint is sparse.

4c. Anticancer and Chemopreventive Activity

Squalene acts as a protective agent and has been shown to decrease chemotherapy-induced side effects. Moreover, squalene alone exhibits chemopreventive activity. Although it is a weak inhibitor of tumor cell proliferation, it contributes either directly or indirectly to the treatment of cancer due to its potentiation effect.

Experimental studies have shown that squalene can effectively inhibit chemically induced skin, colon, and lung tumorigenesis in rodents. The protective effect is observed when squalene is given before and/or during carcinogen treatment.

Experimental data suggest that squalene is involved in the biochemical way by which anticancer drugs act. It seems that squalene may stop tumor cells' development, prevent some forms of chemically induced cancer, and even produce regression of existing tumors in some cases.

The oral administration of squalene has been reported to attenuate cyclophosphamide-induced oxidative damage to the heart, red blood cells, and related tissues.

Evidence strength: Evidence for anticancer activity comes largely from rodent and cell-culture models. No prospective human clinical trials have established squalene as an anticancer or chemopreventive intervention. This area remains preclinical.

4d. Immunological Effects and Vaccine Adjuvancy

The MF59® adjuvant is a squalene-based, oil-in-water emulsion shown to induce robust anti-HA titers to homologous and heterologous strains in humans and to protect against lethal challenge to heterologous influenza in mouse models. The adjuvant effect of MF59 to enhance antibody and T-cell responses has been extensively studied, demonstrating promotion of T-cell activation and B-cell expansion as well as other T-cell-mediated immune responses.

Many clinical trials have shown the squalene-based adjuvant MF59 to increase the immunogenicity of both seasonal and pandemic influenza vaccines, to enhance long-term antibody persistence, and importantly, to promote cross-reactive antibody responses.

MF59-adjuvanted influenza vaccines demonstrated better immunogenicity against specific vaccine virus strains compared to non-adjuvanted influenza vaccines both in healthy adults (RR = 2.10; 95% CI: 1.28–3.44) and the healthy aged (RR = 1.26; 95% CI: 1.10–1.44). The quality of evidence is moderate to high for seroconversion and seroprotection rates of influenza vaccines.

Evidence strength: Strong clinical evidence supports squalene as a vaccine adjuvant component (MF59) across numerous Phase II/III clinical trials involving tens of thousands of participants. This is the most robustly documented human application of squalene.

4e. Skin Health and Dermatological Applications

Squalene, the main component of skin surface polyunsaturated lipids, shows some advantages for the skin as an emollient and antioxidant, and for hydration and its antitumor activities. Squalene appears to be critical for reducing free radical oxidative damage to the skin. Serum squalene originates partly from endogenous cholesterol synthesis and partly from dietary sources, especially in populations consuming large amounts of olive oil or shark liver.

Squalane, a highly stable derivative of squalene, has received attention for its potential application in dermatology and cosmetics due to its biocompatibility, moisturizing properties, and antioxidant activity. A study investigated the effects of squalane on UVA-induced oxidative stress, inflammation, deregulation of collagen metabolism, and signaling pathways in human dermal fibroblasts (HDFs). It was found that squalane at concentrations of 0.005–0.015% counteracted the UVA-induced inhibition of oxidative stress, collagen biosynthesis, prolidase activity, expression of the β1-integrin receptor, insulin-like growth factor-I receptor (IGFR), transforming growth factor-β (TGF-β), phosphorylated kinases ERK1/2, and increase in the expression of p38 kinase in HDFs. Moreover, squalane at the studied concentrations counteracted UVA-induced increase in the expression of NF-κB and COX-2 in HDFs, suggesting its anti-inflammatory activity.

Topical treatments with niacinamide, panthenol, glycerin, allantoin, or squalene may be soothing in the context of radiation dermatitis.

Evidence strength: In vitro cell culture data support antioxidant and anti-inflammatory skin effects. Clinical human data in dermatology remain limited, with most evidence being ex vivo or cell-based.

4f. Blood Pressure and Metabolic Effects

Martirosyan and colleagues reported that squalene-rich amaranth oil reduces systolic blood pressure in a concentration-dependent way. Liu et al. showed that orally administered squalene for four weeks in rats diminished both plasma lipids and blood pressure, probably through a reduction in circulating levels of leptin.

Evidence strength: Animal data only. No replicated controlled human trials specifically examining squalene's effect on blood pressure have been identified.

5. Body Systems and Health Areas Associated with Squalene

• Cardiovascular system: Evidence of squalene having beneficial effects against CVD revealed that the mechanism was similar to that of statins, which was associated with the inhibitory activity on HMG-CoA reductase in the liver, and downregulates the conversion from acetyl CoA to cholesterol.
• Immune system: Squalene has exceptional properties, such as its antioxidant activity, a high penetrability of the skin, and the ability to trigger the immune system, promoting its application in the cosmetic, sustenance, and pharmaceutical industries.
• Integumentary system (skin): Squalene is a structurally unique triterpene compound that is one of the main components (about 13%) of skin surface lipids.
• Endocrine/steroid pathway: The most relevant plant sources of squalene include oils extracted from amaranth, olive, and rice. It is a metabolic intermediate of the sterol biosynthetic pathway and represents a possible target in different metabolic and oxidative stress-related disorders.
• Drug delivery: All of these qualities have rendered squalene a potentially interesting excipient for pharmaceutical applications, especially for the delivery of vaccines, drugs, genes, and other biological substances.

6. Dosage Forms and Reported Dosages

Squalene is available in several forms:

• Oral capsules/softgels: Typically standardized shark liver oil preparations. In one human study, the dose used was 1,500 mg shark liver oil (providing 582 mg as squalene) daily for eight weeks. This dose was selected as it was found to be well tolerated in preliminary toxicological studies, and is also the dose most often taken by individuals using shark liver oil-containing supplements.
• Vaccine adjuvant (MF59): In clinical studies, each 0.5 mL dose of MF59-adjuvanted vaccine contained 9.8 mg of MF59 adjuvant.
• Topical preparations: In in vitro dermatological research on human dermal fibroblasts, squalane at concentrations of 0.005–0.015% was studied for effects on UVA-induced oxidative damage.
• Animal/experimental diets: Dosing in animal studies has varied widely; for example, hamsters were supplemented with 0.1% squalene for 45 days in one study examining lipid effects.

No consensus clinical dosage has been established for squalene as a standalone oral dietary supplement in humans. The dosages described above reflect only what has been reported in cited research contexts and should not be interpreted as clinical recommendations.

7. Safety Considerations

General Toxicological Profile

In general, squalene has an excellent safety profile: it is nonirritating, nonallergenic, poorly absorbed through the gastrointestinal tract, slowly absorbed through the skin, and has low toxicity by all routes, with an oral LD₅₀ of 5 g/kg.

Squalene is well tolerated and active in both humans and rodents, and its clearance from the circulation is slower than that of triglycerides and plant sterols.

Cholesterol Concerns

Among various biological effects, a major focus has been placed on the effect on lipid profiles, as squalene is well-known as a biochemical precursor of cholesterol, leading to the possibility that orally administered squalene may increase serum levels of cholesterol; however, this possibility is challenged by a substantial number of existing in vitro and in vivo studies demonstrating that exogenous squalene exhibits feedback inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a key enzyme functioning in cholesterol biosynthesis.

Absence of Anti-Squalene Antibody Induction

Using a validated enzyme-linked immunosorbent assay for the quantitation of IgG and IgM antibodies against squalene, researchers demonstrated that anti-squalene antibodies are frequently detectable at very low titers in the sera of subjects who were never immunized with vaccines containing squalene. More importantly, vaccination with a subunit influenza vaccine with the MF59 adjuvant neither induced anti-squalene antibodies nor enhanced preexisting anti-squalene antibody titers. In conclusion, anti-squalene antibodies are not increased by immunization with vaccines containing the MF59 adjuvant.

Gulf War Syndrome Controversy

Squalene is a naturally occurring oil which has been used in the development of vaccine adjuvants, such as the oil-in-water emulsion MF59. In past years, by use of non-controlled and non-validated assays, a claim was made that anti-squalene antibodies were detectable in the sera of individuals with the so-called Gulf War syndrome. Subsequent validated studies confirmed that squalene is very poorly immunogenic.

Vaccine Safety Profile

Studies focusing on pandemic H1N1 and prepandemic H5N1 vaccines have shown MF59 to have an acceptable safety profile in children. Transient mild pain or tenderness and erythema were the most commonly reported local reactions, and fatigue and myalgia were the most common systemic reactions. Few, if any, children reported severe reactions including fever above 40°C.

Sustainability and Sourcing Concerns

Intensive fishing for shark-derived squalene has had a devastating impact on marine ecosystems and endangered the populations of squalene-producing shark species. The use of marine animal oil as a source of squalene has also been limited by animal protection regulations and the presence of organic pollutants and heavy metals that may cause cancer concerns in shark-derived material. These considerations have driven the pharmaceutical and cosmetic industries to increasingly seek plant-based and microbially produced alternatives.

Squalene Oxidation Products

Squalene is easily oxidized by molecular oxygen, as a result of which double bonds are converted into an oxidized form by chain reactions in which unsaturated carbon atoms are broken and active oxygen radicals are attached; as a result, saturated forms of the molecule are produced. The biological significance of squalene oxidation products, and whether they pose toxicological concerns, remains an active area of investigation.

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