5-methylcytosine regulated CCNL2 promotes cisplatin resistance by ferroptosis inhibition in ovarian cancer

Ovarian cancer (OC) is the most lethal gynecological tumor, primarily due to resistance to chemotherapy. Cyclin L2 (CCNL2), a novel member of the cyclin family, plays an important role in HIV replication. However, its role in OC chemoresistance remains unknown. Here, we demonstrate that elevated expression of CCNL2 indicates a poor prognosis in ovarian cancer. Furthermore, inhibition of CCNL2 reduces malignancy and enhances chemotherapy sensitivity in OC. Additionally, CCNL2 inhibition promotes cisplatin-induced ferroptosis by increasing intracellular iron ion levels. Mechanistically, CCNL2 is upregulated by YBX1 via a 5-methylcytosine (m5C) manner, leading to increased CCNL2 mRNA stability. Given the lack of protein structure data for CCNL2, we performed virtual screening to identify YBX1 inhibitors, targeting its upstream regulation. The inhibitor YB-B1 effectively suppresses YBX1 and CCNL2 expression, and enhances the cytotoxic effect of cisplatin. Together, we highlight the critical role of CCNL2 in ovarian cancer chemoresistance, elucidate its regulatory mechanism, and propose a new approach to address the challenge.