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

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Abstract
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.
Funding Information
  • National Natural Science Foundation of China (31771972)

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