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Constitutive hepatic mTORC1 activation aggravates alcohol-induced liver injury via endoplasmic reticulum stress-mediated ferroptosis

Lin Xu,Yuanyuan Zhao,Yang Yang,Enbo Qi,Boao Liu,Peili Zhuang,Shiyi Song,Tingmin Chang,Zhiguo Chen,Xiaohong Kang,Xiwen Xiong

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 is a component of the GATOR1 complex, which functions as a repressor of the amino acid-sensing branch of the 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 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, pharmacological relief of ER stress using TUDCA or inhibition of ferroptosis with liproxstatin-1 both alleviated the liver abnormalities induced by Depdc5 ablation in ethanol-fed mice. Additionally, 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.