Demonstrates JOSD1's role in metabolic reprogramming in HCC, suggesting potential for improved immunotherapy outcomes.
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: 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.
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Li et al. (2026) studied this question.
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