The cyclin-dependent kinase inhibitor p27 facilitates chemosensitivity by promoting ferroptosis in epithelial ovarian cancer.

Platinum-based chemotherapy remains the cornerstone of the treatment of epithelial ovarian cancer (EOC); however, platinum resistance is a major cause of tumor recurrence and mortality in EOC patients. This study reports the mechanism by which EOC cells develop resistance to cisplatin by inhibiting the ferroptosis. Immunohistochemical analysis of human EOC tissues revealed that low p27 expression significantly correlated with poor response to chemotherapy and unfavorable patient prognosis. Functionally, CRISPR/Cas9-mediated p27 KO increased cisplatin resistance in EOC cells in both in vitro and in vivo models. RNA sequencing and functional assays demonstrated that p27 enhanced cisplatin sensitivity by facilitating drug-induced ferroptosis in EOC cells. Mechanistically, luciferase reporter assays demonstrated that p27 enhanced the transcriptional activity of cytochrome b-245 heavy chain, a key positive regulator of ferroptosis. Moreover, we found that the small molecule inhibitor SKPin C1 significantly enhanced cisplatin's antitumor effect by preventing p27 degradation, both in vitro and in vivo. In conclusion, our findings emphasize the critical role of p27 in triggering ferroptosis, thereby sensitizing EOC cells to cisplatin therapy. These results suggest that therapeutic strategies aimed at enhancing p27 levels may represent a promising approach to overcoming chemoresistance in EOC.