BMAL2 maintains DNA integrity via regulating homologous recombination to promote ovarian clear cell carcinoma tumorigenesis

Ovarian cancer is the most lethal gynecologic malignancy worldwide. Among its subtypes, ovarian clear cell carcinoma (OCCC) is characterized by its intrinsic chemoresistance, poor prognosis, and lack of effective therapies. To date, only ARID1A mutant OCCC has shown modest sensitivity to PARP inhibitors, highlighting the urgent need for novel therapeutic targets. Here, we identified BMAL2, a circadian transcription as a critical DNA integrity regulator in OCCC cells. BMAL2 depletion downregulated RAD51, impaired homologous recombination-mediated DNA repair thereby inhibited cell survival and tumor growth. To pharmacologically target BMAL2, we performed structure-based virtual screening and identified GW-833972A as a small-molecule inhibitor that effectively bound and degraded BMAL2 protein. Mechanistically, GW-833972A mediated BMAL2 degradation impaired DNA repair and suppressed tumor growth in vivo . Collectively, these findings reveal the critical oncogenic role of BMAL2 in OCCC and demonstrate that BMAL2 inhibition offers a promising therapeutic strategy for this chemoresistant cancer.