Dual miRNA-Mediated Axes Act in Concert in the Antioxidant Action of Eicosapentaenoic Acid: let-7c-3p/TFAM Drives Mitochondrial Biogenesis While miR-34c-5p/SIRT1 Potentiates Enzymatic Defenses.

Previous transcriptomic analysis revealed that eicosapentaenoic acid (EPA) alters miRNA expression in HepG2 cells. Two key miRNA-mRNA axes mediating EPA's antioxidant effects were identified. EPA was found to downregulate let-7c-3p, which directly targets mitochondrial transcription factor A (TFAM). Inhibiting let-7c-3p or overexpressing TFAM enhanced antioxidant capacity, reduced reactive oxygen species, improved mitochondrial function, and promoted mitochondrial biogenesis. In parallel, EPA was found to upregulate miR-34c-5p, which directly targets NAD-Dependent Protein Deacetylase Sirtuin (SIRT1). This repression of SIRT1 is associated with increased activities of antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. These findings indicate a dual-miRNA mechanism through which EPA alleviates oxidative stress via coordinated enhancement of mitochondrial biogenesis and enzymatic defenses.