PPIL2 suppression induces cellular senescence and inhibits proliferation in hepatocellular carcinoma via c-myc/p21 axis.

Hepatocellular carcinoma (HCC) is the most prevalent primary malignancy of the liver characterized by high mortality rates. While peptidylprolyl isomerase-like two (PPIL2) has been implicated in various malignancies, its functional contribution to HCC progression and the underlying molecular mechanisms remain poorly defined. In this study, we observed significant upregulation of PPIL2 in HCC tissues, which correlated with unfavorable patient prognosis. Functional assays showed that PPIL2 knockdown markedly inhibited HCC cell proliferation by inducing cell cycle arrest and cellular senescence. Mechanistically, PPIL2 depletion led to reduced c-Myc protein levels and a concomitant induction of p21. Critically, the tumor-suppressive effects induced by PPIL2 silencing were partially rescued upon c-Myc overexpression, confirming that PPIL2 exerts its oncogenic function predominantly through a c-Myc-dependent pathway. Furthermore, PPIL2 deficiency effectively hindered tumor growth in a xenograft mouse model. Collectively, these findings identify the PPIL2/c-Myc/p21 axis as a critical regulator of HCC proliferation and senescence, positioning PPIL2 as a promising therapeutic target.