FTO-mediated m6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis

The activation of hepatic stellate cells (HSCs) is the central link in the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSCs activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals and N6-methyladenosine (m6A) modification is closely related to autophagy. In this study, we find that m6A demethylase fat mass and obesity-associated protein (FTO) is upregulated during HSCs activation and bile duct ligation (BDL)-induced hepatic fibrosis, which is the m6A methylase with the most significant difference in expression. Importantly, we identify that FTO overexpression aggravates HSCs activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is the target of FTO due to FTO mainly mediates the m6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and activation of HSCs. Noteworthy, m6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level via recognizing the m6A binding site and ultimately inhibits autophagy and activation of HSCs. Taken together, our findings highlight m6A-dependent ULK1 as an essential regulator of HSCs autophagy and reveal ULK1 as a novel potential therapeutic target for hepatic fibrosis treatment. Graphical Abstractm6A demethylases FTO promoted autophagy via recognizing the ULK1 m6A binding site, thus triggering HSCs activation, and eventually leading to liver fibrosis. In this process, YTHDC2 participated in the translation of ULK1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/584975v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@4fdd01org.highwire.dtl.DTLVardef@136791forg.highwire.dtl.DTLVardef@149f448org.highwire.dtl.DTLVardef@44ca9c_HPS_FORMAT_FIGEXP M_FIG C_FIG