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MicroRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and a central player in liver biology and disease. Herein, we report a previously unknown role for miR-122 in hepatocyte intrinsic innate immunity. Restoration of miR-122 levels in hepatoma cells markedly enhanced the activation of interferons (IFNs) in response to a variety of viral nucleic acids or simulations, especially in response to hepatitis C virus RNA and poly (I:C). Mechanistically, miR-122 downregulated the phosphorylation (Tyr705) of STAT3, thereby removing the negative regulation of STAT3 on IFN-signaling. STAT3 represses IFN expression by inhibiting interferon regulatory factor 1 (IRF1), whereas miR-122 targets MERTK, FGFR1 and IGF1R, three receptor tyrosine kinases (RTKs) that directly promote STAT3 phosphorylation. This work identifies a miR-122–RTKs/STAT3–IRF1–IFNs regulatory circuitry, which may play a pivotal role in regulating hepatocyte innate immunity. These findings renewed our knowledge of miR-122’s function and have important implications for the treatment of hepatitis viruses.