TRIM22 induces cellular senescence in hepatocellular carcinoma (HCC) by targeting PHLPP2. The study shows that TRIM22, an E3 ubiquitin ligase, is upregulated by p53 in HCC cells exposed to ionizing radiation (IR), leading to the degradation of the AKT phosphatase PHLPP2. This degradation activates the AKT-p53-p21 signaling pathway, resulting in cellular senescence. Mechanistically, the SPRY domain of TRIM22 directly interacts with the C-terminal domain of PHLPP2, which contains phosphorylation sites regulated by IKKβ. TRIM22-mediated PHLPP2 degradation increases AKT phosphorylation, promoting senescence. In both human HCC databases and patient specimens, TRIM22 and PHLPP2 levels are inversely correlated at the mRNA and protein levels. These findings suggest that TRIM22 modulates PHLPP2 proteasomal degradation to regulate cancer cell senescence, indicating its potential as a therapeutic target for HCC treatment. The study also reveals that TRIM22 physically interacts with PHLPP2 and promotes its ubiquitin-mediated degradation, leading to cellular senescence. Phosphorylation of PHLPP2 by IKKβ is crucial for the interaction between PHLPP2 and TRIM22, and this process is essential for PHLPP2 degradation. TRIM22 expression is inversely correlated with PHLPP2 expression in HCC patient tissues, highlighting its role in HCC progression. Overall, TRIM22 plays a critical role in inducing cellular senescence in HCC by modulating PHLPP2 levels through the ubiquitin-proteasome system.TRIM22 induces cellular senescence in hepatocellular carcinoma (HCC) by targeting PHLPP2. The study shows that TRIM22, an E3 ubiquitin ligase, is upregulated by p53 in HCC cells exposed to ionizing radiation (IR), leading to the degradation of the AKT phosphatase PHLPP2. This degradation activates the AKT-p53-p21 signaling pathway, resulting in cellular senescence. Mechanistically, the SPRY domain of TRIM22 directly interacts with the C-terminal domain of PHLPP2, which contains phosphorylation sites regulated by IKKβ. TRIM22-mediated PHLPP2 degradation increases AKT phosphorylation, promoting senescence. In both human HCC databases and patient specimens, TRIM22 and PHLPP2 levels are inversely correlated at the mRNA and protein levels. These findings suggest that TRIM22 modulates PHLPP2 proteasomal degradation to regulate cancer cell senescence, indicating its potential as a therapeutic target for HCC treatment. The study also reveals that TRIM22 physically interacts with PHLPP2 and promotes its ubiquitin-mediated degradation, leading to cellular senescence. Phosphorylation of PHLPP2 by IKKβ is crucial for the interaction between PHLPP2 and TRIM22, and this process is essential for PHLPP2 degradation. TRIM22 expression is inversely correlated with PHLPP2 expression in HCC patient tissues, highlighting its role in HCC progression. Overall, TRIM22 plays a critical role in inducing cellular senescence in HCC by modulating PHLPP2 levels through the ubiquitin-proteasome system.