IngredientsHeneicosapentaenoic acid (abbreviated HPA) is a long-chain, odd-chain omega-3 polyunsaturated fatty acid (PUFA). It contains 21 carbons and five double bonds, with the systematic shorthand C21:5 n-3. Its full IUPAC systematic name is 6Z,9Z,12Z,15Z,18Z-heneicosapentaenoic acid, also rendered as (all-Z)-6,9,12,15,18-heneicosapentaenoic acid or (6Z,9Z,12Z,15Z,18Z)-6,9,12,15,18-henicosapentaenoic acid. Its CAS registry number is 24257-10-1, and it carries the synonyms FA 21:5 and HPA. Its molecular formula is C21H32O2, and its molecular weight is 316.5 g/mol. The compound is catalogued in the LIPID MAPS Structure Database under LMID LMFA01030823.
HPA's chemical composition is similar to eicosapentaenoic acid (EPA) except that it is elongated with one carbon on the carboxyl end, placing the first double bond in the Δ6 position. All the double bonds of HPA are thereby displaced one carbon away from the carboxyl group when compared to EPA. This structural displacement means that, while both molecules carry five methylene-interrupted cis double bonds and share an omega-3 terminus, HPA's bond arrangement is shifted one methylene unit toward the carboxyl terminus relative to EPA. HPA is thus classified as an odd-chain long-chain PUFA — a class that is comparatively rare among dietary and supplemental fatty acids. It is an odd-chain omega-3 polyunsaturated fatty acid.
HPA is a 21:5 omega-3 fatty acid present in trace amounts in the green alga Bryopsis pennata and in fish oils. Bryopsis pennata is a siphonous green macroalga belonging to the order Bryopsidales, found in shallow marine environments in tropical and subtropical seas. The presence of HPA in this species has made it a recognized, if minor, botanical reference source. No studies to date have reported the isolation or commercial production of HPA directly from algal biomass at scale.
HPA is present in small amounts in fish oils. As is the case for all marine long-chain PUFAs, the ultimate biosynthetic origin of HPA in fish lies in the marine food web: fish do not synthesize omega-3 fatty acids themselves, but rather obtain them via their food supply, including algae or plankton. Accordingly, HPA found in fish oils likely originates from marine microalgae or phytoplankton consumed by fish. The concentrations of HPA in fish oils are low and have not been quantified in standardized dietary terms; it remains a minor constituent compared to EPA (20:5n-3) and DHA (22:6n-3), the dominant omega-3 acids in fish oil.
HPA is also encountered endogenously in mammals as a metabolic product. DHA-H (2-hydroxy-docosahexaenoic acid) undergoes α-oxidation to generate the heneicosapentaenoic acid (HPA, C21:5, n-3) metabolite, an odd-chain omega-3 polyunsaturated fatty acid that accumulates in cell cultures, mouse blood plasma and brain tissue upon DHA-H treatment, reaching higher concentrations than those of DHA-H itself.
Because HPA occurs in such small quantities in natural sources, it is not commercially available as a consumer supplement extracted from fish or algae. For research purposes, HPA has been prepared by chemical elongation of eicosapentaenoic acid (EPA), and its biological properties have been compared with EPA and docosahexaenoic acid (DHA) in laboratory settings. Research-grade preparations are sold as a solution in ethanol at high purity (≥95%) for biochemical and pharmacological investigation. No standardized dietary supplement monograph, pharmacopoeial specification, or commercially available consumer supplement specifically featuring HPA as an isolated ingredient has been identified in authoritative sources.
No traditional or historical use of heneicosapentaenoic acid as an isolated compound has been documented in any pharmacopoeial monograph, WHO monograph, ESCOP monograph, or German Commission E assessment, as HPA was not characterized as a discrete substance until modern analytical chemistry. HPA has not been widely recognized historically as a separate entity in the way that other omega-3 fatty acids like EPA and DHA have been, and no records attribute specific traditional uses specifically to this molecule.
Its natural occurrence in fish oils and marine algae means that populations consuming diets rich in these foods would have ingested trace quantities of HPA alongside EPA, DHA, and other co-occurring fatty acids. Historically, the consumption of marine oils, seaweeds, and certain cold-water fish — natural sources of HPA — has been linked to improved cardiovascular and cognitive health in various traditions. However, these historical health associations pertain to the totality of nutrients in those foods rather than to HPA specifically, and no pre-modern or folk medical tradition attributed health outcomes to HPA as a distinct compound. The molecule was not isolable, characterizable, or even conceptualized as an entity distinct from "fish oil" or "marine fat" prior to modern lipid analytical methods.
HPA belongs to the fatty acid lipid class. Its chemical composition is similar to EPA except elongated with one carbon on the carboxyl end, placing the first double bond in the Δ6 position. All five double bonds are in the cis (Z) configuration and are methylene-interrupted, as is characteristic of long-chain PUFAs from the omega-3 series. The compound is classifiable as an odd-chain fatty acid by virtue of its 21-carbon backbone — an uncommon chain length, since most dietary fatty acids carry even numbers of carbons.
A central established observation in the biochemical study of HPA is its efficient incorporation into cellular lipid pools. HPA is incorporated into phospholipids and into triacylglycerol in cell culture to a similar extent as EPA and DHA. This finding, confirmed across multiple experimental models, indicates that cells do not discriminate against HPA in lipid remodeling pathways and that the one-carbon elongation of the backbone relative to EPA does not impair the fatty acid's ability to be activated as an acyl-CoA and esterified into glycerolipids or membrane phospholipids.
Perhaps the most pharmacologically notable biochemical property of HPA is its potent inhibition of arachidonic acid (AA) biosynthesis. HPA is a stronger inhibitor of the conversion of alpha-linoleic acid and dihomo-gamma-linolenic acid to arachidonic acid (AA) in hepatoma cells than are EPA, DHA, and AA itself. This effect is of potential downstream relevance because AA is the principal substrate for pro-inflammatory eicosanoid synthesis, and its suppression could reduce the generation of prostaglandins, thromboxanes, and leukotrienes of the 2-series. HPA is incorporated into phospholipids and into triacylglycerol in cell culture and inhibits the conversion of linolenic acid to arachidonic acid in hepatoma cells; it is also a poor substrate for prostaglandin H synthase (PGHS, cyclooxygenase) and for 5-lipoxygenase.
HPA interacts with two pivotal enzymes in eicosanoid biosynthesis in a mechanistically distinctive way. HPA is a poor substrate for prostaglandin H synthase (PGHS) and for 5-lipoxygenase, but it inactivates prostaglandin H synthase as rapidly as do AA, EPA, and DHA. This dissociation — being poorly processed as a substrate yet capable of rapid enzyme inactivation — distinguishes HPA from EPA and AA, which are both effective substrates and inactivators of PGHS. The structural basis for this behavior lies in the altered double-bond positioning: by shifting all double bonds one position toward the carboxyl terminus, the molecule is rendered less amenable to the oxygenation that underlies prostaglandin synthesis, while still capable of engaging with the active site in a manner that leads to enzyme inactivation.
HPA inhibits thromboxane synthesis in isolated platelets as efficiently as EPA. This is an important observation because thromboxane A2 (TXA2) is a potent platelet aggregator and vasoconstrictor whose synthesis proceeds through the PGHS/COX pathway. The inhibition of thromboxane synthesis is considered a key mechanism through which EPA exerts antithrombotic and cardiovascular-protective effects, and HPA appears to match this activity despite its poor substrate status, presumably through enzyme inactivation rather than competitive displacement.
EPA, HPA, and DHA are all weak inducers of acyl-CoA oxidase in hepatoma cells. Acyl-CoA oxidase is the rate-limiting enzyme of peroxisomal β-oxidation, a pathway important for the metabolism of very long-chain and unsaturated fatty acids. The weak induction of this pathway by HPA is comparable to that of EPA and DHA, suggesting that HPA does not markedly alter peroxisomal lipid catabolism.
Research conducted from 2020 onward has revealed that HPA can be generated endogenously in mammalian cells and tissues through the α-oxidation of 2-hydroxy-docosahexaenoic acid (DHA-H). DHA-H does not share metabolic routes with its natural analog DHA; the DHA-H α-hydroxyl group provokes steric hindrance on fatty acid carbon 1, which leads to diminished incorporation into cell lipids and accumulation as free fatty acid in cell membranes, resulting in its metabolism toward HPA via α-oxidation. This endogenous pathway has attracted significant interest in the context of neurodegenerative disease research (see Section 6).
There are no completed human clinical trials of heneicosapentaenoic acid as an isolated dietary ingredient. All existing scientific evidence for HPA specifically derives from in vitro (cell-based) experiments and in vivo animal studies. The following section accurately reflects the nature and strength of evidence currently available.
Evidence type: In vitro (cell culture and isolated platelet studies)
The foundational study of HPA's biological properties was published in 1997 in the journal Lipids by Larsen, Høvik, Bremer, and colleagues at Norsk Hydro Research Centre and the University of Oslo (Norway). The authors reported on HPA's incorporation into lipids and its effects on arachidonic acid and eicosanoid synthesis, published in Lipids 32, 707–714 (1997). The study used rat hepatoma (liver cancer) cell lines and isolated human platelets as experimental systems; it was not a human clinical trial. Key findings included:
Evidence strength assessment: The inhibition of AA synthesis and thromboxane production observed in this landmark study were demonstrated in cell culture and isolated platelet systems. While mechanistically plausible, these findings have not been extended to human clinical trials. The authors themselves noted that given the trace amounts of HPA in fish oils, its contribution to the overall biological effects of fish oil consumption is likely minor, with the possible exception of its strong inhibition of AA synthesis.
Evidence type: In vitro (cell lines) and in vivo (transgenic mouse model)
A more recent body of research has linked HPA to potential neuroprotective effects, primarily through studies exploring its role as the active metabolic intermediate of 2-hydroxy-docosahexaenoic acid (DHA-H), a molecule being developed as a candidate therapy for Alzheimer's disease (AD) by Laminar Pharmaceuticals and researchers at the University of the Balearic Islands, Spain.
A 2020 study published in Frontiers in Cell and Developmental Biology (Parets et al., University of the Balearic Islands) demonstrated for the first time that: DHA-H undergoes α-oxidation to generate the heneicosapentaenoic acid (HPA, C21:5, n-3) metabolite, an odd-chain omega-3 polyunsaturated fatty acid that accumulates in cell cultures, mouse blood plasma and brain tissue upon DHA-H treatment, reaching higher concentrations than those of DHA-H itself. Furthermore, brain levels of HPA were positively correlated with spatial behavior in 5xFAD mice, with virtually no DHA-H detected and the DHA levels unmodified in the brain.
A 2023 abstract published in Alzheimer's & Dementia (Cabot, Parets, Miralles et al.) reported that: DHA-H has been shown to reduce the amyloidogenic processing of Amyloid Precursor Protein (APP), as well as having a neuroprotective effect in cellular models. Once DHA-H enters the cell, it is metabolized via α-oxidation to the fatty acid HPA; results obtained in excitotoxicity models and lipid profile analysis suggest that HPA could be a DHA-H effector. APP processing was assessed in cell cultures of HEK293 and N2a neuroblastoma cell lines and analyzed by western blot; neuroprotective effect of DHA-H and HPA was tested in neuron cells differentiated from SH-SY5Y neuroblastoma cells that were stimulated with NMDA/Ca to induce excitotoxicity. The authors concluded that DHA-H exerts neuroprotection and prevents amyloidogenic processing possibly through its metabolic intermediate HPA, and that HPA appears as a new promising molecule for Alzheimer's therapy.
A follow-up study published in Alzheimer's & Dementia in 2025 (Cabot, Parets, Miralles, Trujillo-Estrada, Gutierrez, Fernández-García, Lladó, Escriba, Torres) examined HPA's effects more directly. DHA-H is metabolized through α-oxidation to yield HPA; this metabolic conversion is considered necessary for the neuroprotective effect of DHA-H. The methods employed: cognitive evaluation was assessed by Radial Arm Maze in 5xFAD mice after 4 months of chronic oral treatment at a daily dose of 20 mg/kg (DHA-H or HPA). The key results were: chronic oral administration of DHA-H or HPA prevented cognitive decline in 5xFAD mice; DHA-H is converted to HPA via α-oxidation in cells and mice; HPA accumulates in 5xFAD mice brain instead of DHA-H after DHA-H treatment; both DHA-H and HPA prevented NMDA/Ca-induced neuron death and the neuroprotective effect of DHA-H was partially reversed in the presence of oxythiamine (an α-oxidation inhibitor); HPA decreased ATP production and mitochondrial respiration capacity in astrocytoma cells. The authors concluded that the metabolic intermediate HPA, stemming from the α-oxidation of DHA-H, emerges as a prospective candidate for Alzheimer's therapy.
A commentary in Frontiers in Cell and Developmental Biology on the 2020 Parets et al. study noted the mechanistic model: DHA-H improves cognition in AD modeling mice by converting to the brain-permeable omega-3 PUFA heneicosapentaenoic acid (HPA); the neuroprotective effects associated with HPA are proposed to be associated with its conversion to other omega-3 PUFAs which, in turn, could enrich brain membranes with liquid-disorder-promoting lipids.
Evidence strength assessment: This is an area of active early-stage research. All findings derive from preclinical models (cell lines and 5xFAD transgenic mice). No human clinical trial of HPA as a standalone compound in Alzheimer's disease or any other neurodegenerative condition has been identified. The mechanistic hypothesis — that α-oxidation of DHA-H generates HPA, which then exerts neuroprotection — is supported by convergent preclinical data, but the mechanism of neuroprotection itself remains to be fully established. Furthermore, the mechanism of action behind the neuroprotective effect of HPA is still unknown. Translation to clinical outcomes in human patients has not yet been demonstrated.
Evidence type: In vitro (isolated platelet studies)
The inhibition of thromboxane synthesis in isolated platelets at efficiency comparable to EPA, as demonstrated in the 1997 Larsen et al. study, represents the primary evidence for a potential antithrombotic effect of HPA. HPA inhibits thromboxane synthesis in isolated platelets as efficiently as EPA. Thromboxane A2 promotes platelet aggregation and contributes to atherothrombosis. The mechanistic basis, as discussed above, appears to be through PGHS inactivation rather than substrate competition. However, no animal models of thrombosis or atherosclerosis have been specifically studied using HPA as the test compound, and no human data exist on HPA's effects on platelet function, coagulation markers, lipid profiles, or cardiovascular events.
Evidence strength assessment: Highly preliminary. The antithrombotic inference is mechanistically reasonable given the platelet data, but is based solely on an in vitro isolated platelet assay. No animal model or clinical cardiovascular data are available for HPA specifically.
Evidence type: In vitro (hepatoma cell culture)
The 1997 Larsen et al. study examined HPA's effect on lipid metabolism in hepatoma cells. HPA is a stronger inhibitor of the conversion of alpha-linoleic acid and dihomo-gamma-linolenic acid to arachidonic acid in hepatoma cells than are EPA, DHA, and AA itself. This inhibitory action on the desaturation-elongation pathway leading to AA suggests a potential mechanism for reducing the cellular availability of AA, the precursor for pro-inflammatory eicosanoids. This observation has not been extended to in vivo models or human studies, and the clinical significance of this in vitro effect is unknown.
Based on the published scientific literature, HPA has been investigated or associated with the following body systems:
No established human dosage for HPA as a dietary supplement or pharmaceutical agent has been defined, as no human clinical trials of HPA have been completed. The only dosages reported in the scientific literature derive from preclinical animal experiments:
As a research-grade biochemical, HPA is commercially available in small quantities (1 mg, 5 mg) as a solution in ethanol at ≥95% purity. These preparations are designated for laboratory research use and are not intended for human administration.
No human safety or tolerability data for isolated HPA as a dietary supplement or drug candidate have been published. Because HPA occurs at trace levels in common foods (fish oils, marine fish), dietary exposure in humans consuming fish or fish oil supplements is incidental and at very low quantities relative to EPA and DHA. No adverse effects attributable to HPA specifically have been reported in the literature.
From its documented biochemical activity, certain interactions can be pharmacologically inferred, though none have been demonstrated clinically:
The authors of the principal biochemical study noted that since fish oils contain only small amounts of HPA, it is unlikely that this fatty acid is of particular significance for the biological effects of these oils, possibly with the exception that it is a strong inhibitor of AA synthesis. This judgment limits the likelihood that incidental dietary exposure to HPA through standard fish oil supplementation would produce meaningful physiological effects attributable to HPA alone.
Heneicosapentaenoic acid is a structurally distinctive odd-chain, 21-carbon omega-3 PUFA found in trace amounts in fish oils and in the green alga Bryopsis pennata. Its chemical structure is defined by its one-carbon elongation relative to EPA, displacing all five double bonds by one position toward the carboxyl group. The published biochemical evidence, primarily from a seminal 1997 study by Larsen et al. and a series of more recent preclinical neuroprotection studies (2020–2025), establishes several noteworthy in vitro and animal-model properties: efficient incorporation into cellular phospholipids and triacylglycerols; exceptionally potent inhibition of arachidonic acid biosynthesis in hepatoma cells; rapid inactivation of prostaglandin H synthase; efficient inhibition of thromboxane synthesis in isolated platelets; and preclinical evidence of neuroprotection and prevention of cognitive decline in an Alzheimer's disease mouse model (5xFAD), where it acts as the proximal active metabolite of 2-hydroxy-DHA.
No human clinical trials of HPA as an isolated supplement or drug candidate have been completed. No established human dietary reference intake, pharmacopoeial monograph, or regulatory health claim applies to this compound. All evidence remains at the preclinical (cell culture and animal model) stage. Key research gaps include: human pharmacokinetics and bioavailability; human safety, tolerability, and dose-response data; confirmation of eicosanoid-modulating effects in human subjects; and clinical translation of the Alzheimer's disease findings observed in mouse models. Comprehensive clinical studies on HPA are limited compared to its better-known counterparts, and continued investigation and clinical validation are needed to define HPA's precise role in human nutrition and wellness.
Health conditions that Heneicosapentaenoic acid may help support.
Body systems that Heneicosapentaenoic acid may help support.
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