Torin1

Alcohol-related liver disease (ALD), a consequence of excessive alcohol use, manifests across a broad spectrum of liver damage, ranging from steatosis to cirrhosis. DEPDC5 (DEP domain-containing protein 5) is a component of the GATOR1 (gap activity towards rags 1) complex, which functions as a repressor of the amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In this study, hepatocyte-specific Depdc5 knockout mice (Depdc5^△Hep) were generated, and it was found that aberrant activation of mTORC1 caused by Depdc5 deletion led to exacerbated endoplasmic reticulum (ER) stress and hepatocyte ferroptosis in the livers of ethanol-fed mice. Torin-1, an ATP-competitive mTOR inhibitor, suppressed the mTORC1 activity and reversed the effects of Depdc5 deletion on ER stress and ferroptosis in ethanol-fed mouse livers. Furthermore, pharmacologic relief of ER stress using tauroursodeoxycholic acid or inhibition of ferroptosis with liproxstatin-1 both alleviated the liver abnormalities induced by Depdc5 ablation in ethanol-fed mice. In addition, the research uncovered that ER stress functions as an upstream signal of ferroptosis in the progression of ALD. These findings provide novel in vivo evidence that sustained mTORC1 activation leads to alcoholic liver injury by inducing ER stress and ferroptosis, suggesting that targeting these pathways may represent a potential therapeutic strategy for ALD.