Abstract

Lipophagy, a selective form of macroautophagy/autophagy, degrades lipid droplets (LDs) to provide energy and is implicated in metabolic disorders. The molecular mechanism underlying lipophagy induction remains incompletely understood. This study explored the role of SETDB1 in starvation-induced autophagy and lipophagy. We demonstrate that SETDB1 deficiency exacerbates starvation-induced hepatic lipid accumulation by inhibiting lipophagy. Mechanistically, starvation promotes ATM-mediated phosphorylation of SETDB1, which enhances its interaction with and methylation of the RNA helicase DDX5. In SETDB1-knockout hepatocytes, hypomethylation of DDX5 facilitates the formation of the DDX5-METTL3-METTL14 complex, increasing m6A modification of BECN1 and TFEB mRNAs. This modification promoted YTHDF2-mediated decay of these transcripts, thereby inhibiting starvation-induced autophagy and lipophagy. Furthermore, administration of the SETDB1 activator (R, R)-59 significantly enhances lipophagy and attenuates starvation-induced hepatic steatosis. Collectively, our findings reveal a novel pathway in which SETDB1 deficiency drives m6A-mediated mRNA degradation to suppress lipophagy, thereby contributing to hepatic steatosis.