STEAP4-Mediated ROS-TERT-TP53 Signaling Promotes Granulosa Cell Dysfunction in Experimental Models of Polycystic Ovary Syndrome.

Background

Polycystic ovary syndrome (PCOS) is a frequently encountered endocrine disturbance with a still poorly defined etiology that arises in women during their reproductive years. Increased apoptosis of granulosa cells has been identified as one of the key factors contributing to abnormal follicular development. This study aimed to elucidate the role of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in granulosa cell function using in vitro and in vivo models relevant to PCOS.

Methods

We treated KGN cells (a human granulosa-like cell line) and C57BL/6 mice with dehydroepiandrosterone (DHEA) to establish experimental models mimicking PCOS features. STEAP4 expression was assessed by qRT-PCR, Western blot, and immunohistochemistry. Proliferative capacity and apoptotic rates were gauged with CCK-8 assays, EdU labeling, and flow cytometry. The regulatory mechanisms were investigated through immunofluorescence staining for nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation and immunoprecipitation assays for HIF-1α ubiquitination.

Results

Exposure to androgen markedly raised both STEAP4 transcript and protein abundance in KGN cells as well as in PCOS model mice. STEAP4 knockdown resulted in increased proliferation and reduced apoptosis in DHEA-treated KGN cells. Mechanistically, STEAP4 enhanced reactive oxygen species levels, promoted Nrf2 nuclear translocation, and stabilized HIF-1α protein by reducing its ubiquitination, leading to increased TERT expression and subsequent TP53 pathway activation. In vivo, STEAP4 silencing significantly alleviated hormonal imbalances, estrous cycle disorders, and reduced oxidative stress levels in ovarian tissue of DHEA-induced PCOS-like mice.

Conclusions

Taken together, evidence from these experimental models indicates that STEAP4 shapes oxidative stress and granulosa cell apoptosis by operating through the ROS-TERT-TP53 axis. The data point to a possible contribution of STEAP4 to PCOS pathogenesis and mark it as a candidate therapeutic target that merits additional clinical study.