biostudies-literatureXu HNational Basic Research Program of ChinaNational Key R&D Program of ChinaNational Natural Science Foundation of ChinaNatural Science Foundation of Guangdong Provincee41159https://www.ebi.ac.uk/biostudies/studies/S-EPMC6389286biostudies-literatureUnknown8MicroRNA-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 phosphoreLifeMicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway.PMC6389286312005932017YFA0504400314712232011CB81130031671349312300422014A030313163Xie SJYang JHQu LHZhang YXu SJZheng MNZhang WQXu HZhou HfalseMicroRNA-122 supports robust innate immunity in hepatocytes by targeting the RTKs/STAT3 signaling pathway.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 phosphor2019-01-01T00:00:00Z2019 Feb2026-05-04T08:03:04.521Z2019-06-06T23:24:08ZS-EPMC63892863073512110.7554/eLife.41159