Emerging Pathways of Action of Eicosapentaenoic Acid (EPA) (2025)

Substantial randomized data support the cardiovascular benefits of the omega-3 fatty acid eicosapentaenoic acid (EPA).1, 2, 3, 4 Yet, lack of a clear understanding of the likely multifactorial mechanism of benefit of EPA has generated skepticism among some physicians, potentially leading to underuse of this clinically beneficial, cost-effective, and safe therapy. The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) showed large relative and absolute risk reductions in ischemic events with icosapent ethyl (a highly purified, pharmaceutical grade ethyl ester of EPA), including a significant reduction in cardiovascular death in secondary and high-risk primary prevention patients with mildly to moderately elevated triglycerides.1 Interestingly, the benefit extended across the full range of baseline triglyceride values in the trial, including in the subgroup of patients who entered the trial with normal triglyceride levels.5 Similarly, the benefit of icosapent ethyl extended to those patients who either did or did not achieve triglyceride levels within the normal range during the trial.1 Mediation analyses suggested that the triglyceride reduction accounted for a minority of the drug’s benefit, with approximately two-thirds of the benefit caused by the large increase in serum EPA that occurred on treatment. However, that observation does not actually explain how the EPA itself exerts its cardioprotective benefits.

In this issue of JACC: Basic to Translational Science, Reilly etal6 explore 1 possible mechanism of benefit of EPA—an anti-inflammatory effect. Studying nonactivated CD4+ T cells, the authors found that EPA reduced expression of immune response-related genes and boosted that of genes that combat oxidative stress. Many anti-inflammatory (and antioxidant) actions were specific to EPA and were not seen with oleic acid or palmitic acid, or control comparators. The novel observations from this paper greatly advance our understanding of the multitude of biological actions of EPA.

The transcriptomic analysis showed that EPA may prevent CD4+ T cell activation and subsequent differentiation by decreased transcription of genes critical to these T cell processes, including CD69 and IL2RA, respectively.6 Such changes occurred concomitant with decreased expression of transcription factors implicated in T cell differentiation, indicating a robust effect of EPA on these cells. Of particular interest, the transcriptomic analysis of nonactivated T cells revealed that EPA treatment modulated genes whose protein products were similarly expressed in other tissues, including human endothelial cells, indicating the presence of conserved mechanisms of action with EPA across multiple cell types.6^,7 In both T cells and endothelial cells, EPA treatment specifically increased transcription of HMOX1 and NQO1, which encode for the proteins heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), respectively.6^,7 These genes are among those located within a nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant response element that controls DNA transcription. In endothelial cells, EPA treatment significantly increased both HO-1 and NQO1 following IL-6 challenge.7 EPA enhances NRF2 translocation to the nucleus followed by transcription (and subsequent translation) of the cassette of genes influenced by the antioxidant response element. Thus, these new transcriptomic findings support systemic effects of EPA on particular pathways involved in the regulation of immune function, as previously reported in the vascular endothelium.6^,7

Endothelial dysfunction and inflammation drive atherosclerosis and, if uninterrupted, can culminate with plaque rupture and thrombosis (Figure1). A growing body of basic research, such as these T cell transcriptomic data, adds to our understanding of how EPA may modify atherosclerosis at multiple points to contribute mechanistically to the overall cardiovascular risk reduction noted in the outcome trials. Beyond reductions in inflammation and T cell activation, EPA improves endothelial vasodilator function and nitric oxide bioavailability while interrupting cholesterol crystallization and lipid oxidation even compared with other long chain fatty acids.8

Inflammation contributes centrally to the genesis of plaque rupture and ischemic events. Contemporary data support that the risk associated with arterial inflammation persists independently of low-density lipoprotein cholesterol and triglyceride levels.9 The data from Reilly etal6 suggest that EPA could help address this component of residual cardiovascular risk. Analyses from REDUCE-IT show consistent clinical benefits of EPA across baseline levels of low-density lipoprotein cholesterol (and triglycerides, as noted in the previous text). Anti-inflammatory effects mediated by the adaptive immune modulation beyond those assessed by the biomarkers of innate immunity previously reported in REDUCE-IT, such as the effects on T cells reported by Reilly etal,6 could contribute to these benefits.

The valuable data from Reilly etal6 add to other important experimental data that have shown cell membrane stabilizing properties, other anti-inflammatory effects, antioxidant benefits, and antithrombotic properties of EPA, beyond its ability to lower levels of triglyceride-rich lipoproteins.8 These laboratory data complement several randomized imaging trials that also show effects of EPA on slowing or even reversing coronary plaque progression, including the first demonstration of an effect of any drug on improving noninvasively determined fractional flow reserve on CT angiography.10

The present analysis should prompt further research on EPA. This molecule, highly conserved through evolution, appears to play a fundamental role in cardiovascular biology. In REDUCE-IT, no apparent excess in infections emerged; thus, unlike some other targeted anti-inflammatory agents, there does not appear to be an infectious disease risk associated with EPA. This observation opens the door to the study of EPA in other disease states where the effects described by Reilly etal6 on T cells may also provide clinical benefit.

Carefully performed basic science experiments such as the current ones by Reilly etal6 should help convince physicians that data from REDUCE-IT and several other consistent clinical and imaging trials have a firm biological basis. Hopefully, this deeper understanding of the emerging pathways of action of EPA (Figure1) will translate into appropriate patients being identified and treated with icosapent ethyl in daily practice.