Targeting mTORC2-Dependent AKT/FOXO1/RNF125 Signaling Exploits a Therapeutic Vulnerability in c-MET-Activated and β-catenin-Mutated Hepatocellular Carcinoma

Background and Aims: Approximately 10% of human hepatocellular carcinomas (HCC) exhibit concurrent c-MET activation and β-catenin gain-of-function mutations, representing a clinically relevant HCC subtype. This study aimed to investigate the role of mTORC2/AKT signaling in this subtype and identify potential therapeutic targets. Approach and Results: The mTORC2/AKT cascade was activated in c-Met/β-cateninΔ90 HCC lesions. Genetic ablation of Rictor, the essential mTORC2 subunit, strongly suppressed c-Met/β-cateninΔ90-dependent hepatocarcinogenesis. Mechanistically, both the TSC2/mTORC1 axis and FOXO1 transcription factors functioned as critical downstream effectors of mTORC2/AKT in this model. We further identified RNF125 as a direct transcriptional target of FOXO1. RNF125 overexpression significantly inhibited tumorigenesis in the c-Met/β-cateninΔ90 model and suppressed liver cancer cell growth in vitro. Notably, using an in vivo doxycycline-inducible system, we found that inducing RNF125 expression in established c-Met/β-cateninΔ90 HCC suppressed tumor progression, suggesting that activation of RNF125 may have translational implications for HCC treatment. Conclusions: Our study, for the first time, established the mTORC2/AKT/FOXO1/RNF125 axis as a critical driver and therapeutic vulnerability in c-MET-activated/β-catenin-mutated HCC. Our study filled a critical gap by defining the tumor-suppressive role of FOXO1 specifically in this HCC subtype. Furthermore, our results positioned RNF125 as a promising therapeutic target for this aggressive HCC subtype.