The Lysine Methyltransferase SETDB1 Alleviates Methionine- and Choline-Deficient Diet-Induced Steatohepatitis by Suppressing Ferroptosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder, with its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), characterized by steatosis, inflammation, hepatocyte injury, and fibrosis. However, the underlying mechanism remains incompletely understood. Here, we performed an in vivo CRISPR screen in Cas9 mice fed a methionine- and choline-deficient (MCD) diet to identify epigenetic regulators of MASH. SETDB1 emerged as a key modulator: hepatocyte-specific loss of Setdb1 exacerbated steatosis, inflammation, ductular reaction, and fibrosis, whereas Setdb1 overexpression markedly alleviated these pathological features. Notably, human liver samples showed decreased SETDB1 expression with advancing MASLD. Furthermore, SETDB1 deficiency increased hepatic ferroptosis by upregulating ACSL4, aggravating MASH pathology, whereas ACSL4 knockout reduced liver injury in the absence of SETDB1. SETDB1 overexpression protected against liver damage by repressing ACSL4. Therefore, the SETDB1-ACSL4-ferroptosis axis regulates MASH progression and represents a potential therapeutic target.