The study investigates the role of TRIM22 in cellular senescence in hepatocellular carcinoma (HCC). TRIM22, an E3 ubiquitin ligase, is upregulated by p53 in HCC cells undergoing ionizing radiation (IR)-induced senescence. Overexpression of TRIM22 triggers cellular senescence by targeting the AKT phosphatase, PHLPP2. Mechanistically, TRIM22 directly binds to the C-terminal domain of PHLPP2, leading to its degradation via the ubiquitin-proteasome pathway. This degradation activates the AKT-p53-p21 signaling pathway, ultimately resulting in cellular senescence. In both human HCC databases and patient specimens, TRIM22 and PHLPP2 levels show inverse correlations at both mRNA and protein levels. These findings suggest that TRIM22 regulates cancer cell senescence by modulating the proteasomal degradation of PHLPP2 in HCC cells, highlighting its potential as a therapeutic target for cancer treatment.The study investigates the role of TRIM22 in cellular senescence in hepatocellular carcinoma (HCC). TRIM22, an E3 ubiquitin ligase, is upregulated by p53 in HCC cells undergoing ionizing radiation (IR)-induced senescence. Overexpression of TRIM22 triggers cellular senescence by targeting the AKT phosphatase, PHLPP2. Mechanistically, TRIM22 directly binds to the C-terminal domain of PHLPP2, leading to its degradation via the ubiquitin-proteasome pathway. This degradation activates the AKT-p53-p21 signaling pathway, ultimately resulting in cellular senescence. In both human HCC databases and patient specimens, TRIM22 and PHLPP2 levels show inverse correlations at both mRNA and protein levels. These findings suggest that TRIM22 regulates cancer cell senescence by modulating the proteasomal degradation of PHLPP2 in HCC cells, highlighting its potential as a therapeutic target for cancer treatment.