CCDC134 enhances ovarian reserve function and angiogenesis by directly interacting with INHA in a mouse model of premature ovarian insufficiency.

Abstract

Premature ovarian insufficiency (POI) is a multifactorial condition characterized by diminished ovarian function, granulosa cell (GC) apoptosis, and impaired ovarian angiogenesis, leading to infertility and long-term health complications. Despite its prevalence, effective therapeutic targets for POI remain limited. This study investigates the role of CCDC134 in maintaining ovarian reserve and promoting angiogenesis and its interaction with INHA in a mouse model of POI. Ovarian granulosa cells from POI patients and unaffected women were analyzed for apoptosis and CCDC134 expression. A cisplatin-induced mouse model of POI was used to evaluate the therapeutic potential of AAV-mediated ovary-specific overexpression of CCDC134. Ovarian morphology, hormonal levels, follicular development, granulosa cell viability, and angiogenesis were assessed. The interaction between CCDC134 and INHA was examined using co-immunoprecipitation, immunofluorescence, and molecular pathway analyses. CCDC134 expression was significantly downregulated in ovarian tissues and granulosa cells of POI patients and cisplatin-induced POI mice. CCDC134 overexpression improved ovarian morphology, restored follicular development across all stages, and enhanced reproductive outcomes in POI mice. Hormonal imbalances, including decreased AMH and E2 and elevated FSH and LH, were reversed following CCDC134 overexpression. Moreover, CCDC134 treatment significantly reduced GC apoptosis by downregulating pro-apoptotic markers (Caspase-3 and Bax) and upregulating anti-apoptotic Bcl-2. Angiogenesis was enhanced, as indicated by increased expression of CD34 and vWF, improved endothelial cell viability, and restored VEGF levels. Mechanistic studies revealed a direct interaction between CCDC134 and INHA, with CCDC134 promoting INHA expression and modulating apoptotic and angiogenic pathways. CCDC134 plays a critical role in maintaining ovarian reserve and promoting angiogenesis by directly interacting with INHA. Its overexpression restores ovarian function, mitigates granulosa cell apoptosis, and enhances angiogenesis in a mouse model of POI. These findings highlight the therapeutic potential of the CCDC134-INHA axis as a novel strategy for treating POI.