The HKDC1-ASS1-ACSBG2 axis reprograms lipid metabolism to drive therapeutic resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a lethal malignancy characterized by profound metabolic reprogramming, notably aberrant lipid metabolism. Current therapeutic strategies offer limited efficacy, highlighting the critical need to identify its metabolic vulnerabilities. This study aims to investigate the role of the HKDC1-ASS1-ACSBG2 axis in lipid metabolic reprogramming and therapeutic resistance in HCC. Using clinical HCC specimens and cell lines, we systematically evaluated the functions and mechanisms of HKDC1, ASS1, and ACSBG2 in lipogenesis, cell proliferation, and drug response via RNA sequencing, co-immunoprecipitation, immunofluorescence, ubiquitination assays, dual-luciferase reporter assays, cellular functional experiments, and nude mouse xenograft models. HKDC1 was highly expressed in HCC and correlated with poor patient prognosis. Mechanistically, HKDC1 interacts with ASS1 (310–412 aa) via its HKLS1 domain, inhibiting ubiquitin-mediated degradation and stabilizing ASS1. This enhances the production of glutamine-derived acetyl-CoA. The accumulated acetyl-CoA transcriptionally activates ACSBG2 by inducing histone H3 acetylation, thereby driving lipid biosynthesis and HCC cell proliferation. This axis operates distinctly from the FASN-dependent pathway and promotes lenvatinib resistance both in vitro and in vivo. Our study unveils a novel metabolic regulatory axis, HKDC1-ASS1-ACSBG2, that promotes lipogenesis and tumor progression in HCC by integrating multiple metabolic pathways, and confers lenvatinib resistance. Targeting this axis may present a novel therapeutic strategy to overcome treatment resistance in this recalcitrant malignancy.