DHCR24 Drives Ovarian Cancer Chemoresistance Through Lipid Raft-mediated P-gp Stabilization and STAT3 Activation.

OBJECTIVE: To investigate the role and mechanism of DHCR24 in chemoresistance of ovarian cancer and to identify potential therapeutic targets for overcoming treatment resistance. METHODS: We integrated bioinformatic analysis of GEO datasets and clinical survival data from KMplot to identify chemoresistance-associated genes. DHCR24 expression and function were systematically evaluated using cisplatin-resistant cell lines (A2780/DDP, SKOV3/DDP), patient-derived primary cells, xenograft models, and clinical specimens through molecular biology techniques, immunohistochemistry, and functional assays. Mechanistic studies employed RNA interference, cholesterol modulation, lipid raft disruption with MβCD, cycloheximide chase assays, and STAT3 pathway inhibition. RESULTS: DHCR24 was consistently upregulated in chemoresistant ovarian cancer models and significantly correlated with poor patient survival. Genetic or pharmacological inhibition of DHCR24 restored chemosensitivity in vitro and in vivo, while its overexpression induced cross-resistance to multiple chemotherapeutic agents. Mechanistically, DHCR24 enhanced cholesterol biosynthesis, which stabilized lipid raft microdomains to promote P-gp protein stability and facilitate STAT3 membrane recruitment and activation. Furthermore, activated STAT3 transcriptionally upregulated DHCR24 expression, establishing a positive feedback loop that perpetuates the chemoresistant phenotype. CONCLUSION: DHCR24 drives chemoresistance through a cholesterol-dependent circuit that stabilizes drug efflux pumps and activates pro-survival signaling, identifying DHCR24 as a promising therapeutic target for overcoming chemotherapy resistance in ovarian cancer.