JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis

Abstract Hepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. Here, we interestingly found that DEN-induced hepatocarcinogenesis was enhanced while NASH-induced hepatocarcinogenesis was abolished by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIGI expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively monomethylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL6STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Together with clinical data that RIGI was decreased in hepatic precancerous dysplastic nodules while increased in NAFLD, we conclude that decreased RIGI in HcPCs promotes necroinflammationinduced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis.