JOSD1 drives hepatocellular carcinoma malignancy by modulating the ubiquitination-lactylation switch on PGAM1

Background Metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC), enabling rapid tumour growth and immune evasion. Protein post-translational modification (PTM) crosstalk is a critical regulator of cellular processes; however, its contribution to metabolic reprogramming in HCC remains unclear. Objective To elucidate the function of the deubiquitinase JOSD1 in modulating PTM crosstalk and its impact on tumour glycolysis, progression and immunotherapy response in HCC. Design We combined multi-omics analyses with functional and mechanistic studies in cell lines, animal models and patient samples to characterise JOSD1 and its downstream pathways in HCC. Results JOSD1 was identified as a gene associated with glycolysis and correlated with a poor prognosis. Its over-expression promoted malignant phenotypes and enhanced glycolytic flux. Mechanistically, the JOSD1-AARS1 axis cooperatively regulates the ubiquitination-lactylation crosstalk at the K251 residue of PGAM1, thereby stabilising PGAM1, enhancing its enzymatic activity and promoting lactate accumulation. This metabolic shift impaired CD8 + T cell infiltration and function, promoting immune suppression. Therapeutically, liver-targeted inhibition of JOSD1 effectively suppressed tumour progression and synergised with anti-PD-1 therapy, leading to prolonged survival. Conclusion The JOSD1-AARS1 axis regulates the ubiquitination-lactylation crosstalk on PGAM1, with JOSD1 acting as the critical upstream molecular switch that drives metabolic reprogramming and immune evasion in HCC. Targeting JOSD1 represents a promising therapeutic strategy to modulate tumour metabolism and improve immunotherapy efficacy.