KLF5-regulated ZDHHC8 reduces chemosensitivity in high-grade serous ovarian cancer through β-catenin signaling.

High-grade serous ovarian cancer (HGSOC) is a highly aggressive gynecologic malignancy, and chemoresistance remains a major challenge in its treatment. This study identifies ZDHHC8 as a key regulator of chemotherapy sensitivity in HGSOC. Bioinformatics analysis revealed that elevated ZDHHC8 expression correlates with poorer progression-free and overall survival in chemotherapy-treated patients. Immunohistochemical analysis of clinical HGSOC samples further demonstrated that chemoresistant tumors exhibit higher levels of ZDHHC8 than chemotherapy-sensitive ones. In vitro functional assays showed that ZDHHC8 knockdown enhanced chemotherapy sensitivity by decreasing the cisplatin IC50, increasing cisplatin-induced apoptosis, and promoting DNA damage, whereas overexpression experiments reduced cisplatin sensitivity. Mechanistic studies indicated that KLF5, identified as a transcription factor through chromatin immunoprecipitation and luciferase reporter assays, directly binds to the ZDHHC8 promoter and upregulates its expression. Moreover, ZDHHC8 upregulates β-catenin, a key mediator of chemotherapy insensitivity, and its effects are reversed by a β-catenin inhibitor. Animal models further supported the roles of ZDHHC8, KLF5, and β-catenin in regulating chemotherapy sensitivity. Collectively, these results establish the KLF5-ZDHHC8-β-catenin axis as a critical pathway that impairs chemotherapy sensitivity in HGSOC and suggest that targeting ZDHHC8 may improve treatment outcomes.