HBx-mediated GPT2 suppression promotes liver cancer development by downregulating ADH1A

Hepatitis B virus (HBV) is the primary driver of liver cancer (LC), a malignancy characterized by extensive metabolic reprogramming. However, the specific mechanisms linking viral oncoproteins to metabolic dysregulation in LC remain incompletely understood. This study was aimed at investigating the function of the metabolic enzyme GPT2 in hepatocarcinogenesis, focusing on its regulation by HBV X protein (HBx) and its effects on downstream signaling pathways.

We combined analysis of multiple patient cohorts with in vitro and in vivo functional assays to determine the clinical relevance and function of GPT2. Co-immunoprecipitation, ubiquitination assays, and targeted pharmacological or genetic manipulations were used to delineate the signaling cascade.

GPT2 was significantly downregulated in LC, and its low expression correlated with poor patient survival. Functionally, GPT2 loss promoted LC cell proliferation, migration, and lipid accumulation. Mechanistically, GPT2 was found to suppress the mTOR pathway by disrupting the AKT-mTOR interaction and leading to upregulation of ADH1A. In turn, ADH1A facilitates CBL-mediated ubiquitination and degradation of LSD1, a key driver of lipogenesis. Critically, the HBV oncoprotein HBx functions as a molecular adaptor that recruits TRIM25 to GPT2, thus leading to GPT2 ubiquitination and proteasomal degradation. Moreover, HBx-mediated loss of GPT2 was found to drive tumor progression by modulating the mTOR-ADH1A-LSD1 axis and enhancing lipid synthesis.

Our study delineated a novel HBx-TRIM25-GPT2-ADH1A-LSD1 signaling axis promoting virus-associated hepatocarcinogenesis. GPT2 was identified as a critical metabolic tumor suppressor hijacked by HBV and a promising therapeutic target for treating HBV-associated LC.