Abstract

Metabolic dysregulation has been recognized as a crucial driver of tumorigenesis, particularly in metabolic dysfunction-associated steatotic liver disease (MASLD)-related hepatocellular carcinoma (HCC). However, the underlying mechanisms remain poorly understood. Here, we identify lysosome-localized insulin receptor tyrosine kinase substrate (IRTKS) as a key activator of the metabolic master regulator mTORC1 through phospho-antibody array screening. IRTKS forms membrane-associated condensates that selectively interact with the GTPase RRAGD, a key upstream regulator of mTORC1, thereby enhancing the sensitivity of mTORC1 to free amino acids. Notably, in hepatic knockin mice, Irtks-mediated mTORC1 hyperactivation promotes obesity, hepatic lipid accumulation, and the progression from MASLD to metabolic dysfunction-associated steatohepatitis and HCC. Conversely, pharmacological inhibition of mTORC1 or genetic ablation of Irtks ameliorates hepatic steatosis, inflammation, and metabolic dysfunction in mouse models. Our study establishes IRTKS as a central regulator of mTORC1-dependent metabolic reprogramming during hepatocarcinogenesis, providing potential therapeutic targets for MASLD-associated liver cancer.