Highlights
- JOSD1 is identified as a critical deubiquitinase overexpressed in hepatocellular carcinoma (HCC) that correlates with poor clinical outcomes.
- The JOSD1-AARS1 axis regulates a specific ‘ubiquitination-lactylation’ crosstalk at the K251 residue of the glycolytic enzyme PGAM1.
- Elevated JOSD1 stabilizes PGAM1 and enhances its enzymatic activity, leading to massive lactate accumulation and CD8+ T cell exhaustion.
- Targeting JOSD1 via liver-specific delivery systems synergizes with anti-PD-1 therapy to overcome immune resistance in HCC models.
Background
