p65-mediated Mettl3/Mettl14 transactivation and m(6)A-dependent TGF-beta 1 translation aggravates fibrosis progression in nonalcoholic steatohepatitis

N6‐methyladenosine (m 6 A) RNA modification has been reported to play an important role in hepatic carcinoma (HCC). Non‐alcoholic steatohepatitis (NASH) predisposes the progressive development of liver fibrosis, cirrhosis and HCC, yet whether and how m 6 A is involved in the critical transition of NASH to fibrosis remains elusive. Here we demonstrate an up‐regulation of Mettl3/Mettl14 and global m 6 A hypermethylation in the liver of high‐fat diet‐induced NASH and fibrosis rat model, with increased serum lipopolysaccharide (LPS). LPS‐induced profibrotic TGF‐β1 translation in Kupffer cells (KC), which is prevented by Mettl3/Mettl14 knockdown, coincides with higher m 6 A level on 5’UTR of TGF‐β1 mRNA. NF‐κB p65 transactivates Mettl3/Mettl14, which leads to m 6 A‐dependent translation of TGF‐β1 mRNA in a cap‐independent manner . Our findings identify m 6 A modification as a new player in p65‐mediated inflammatory signaling and TGF‐β1‐activated fibrosis progression in NASH. Support or Funding Information This work was supported by the National Key Research and Development Program of China (2016YFD0500502), the National Natural Science Foundation of China (31672512) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). m6A modification is essential in the process of NASH to liver fibrosis by connecting gene transcription with Mettl3/Mettl14. The regulatory role of the classic transcriptional factors NF‐κB p65, that keeps high m6A modification of the TGF‐β1 mRNA 5’UTR provides fundamental insight into the post‐transcriptional gene regulation network in KC activation, revealing potential novel ways to regulate the process of NASH to liver fibrosis. Figure 1