{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:47Z","timestamp":1785410567377,"version":"3.56.0"},"reference-count":49,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271663"],"award-info":[{"award-number":["82271663"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301961"],"award-info":[{"award-number":["82301961"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82271663"],"award-info":[{"award-number":["82271663"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82301961"],"award-info":[{"award-number":["82301961"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Key Research & Development Program of China","award":["2024YFA1108100"],"award-info":[{"award-number":["2024YFA1108100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013PCR, 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\u20132\u2013related factor 2 (Nrf2) nuclear translocation and immunoprecipitation assays for HIF-1\u03b1 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\u2013treated KGN cells. Mechanistically, STEAP4 enhanced reactive oxygen species levels, promoted Nrf2 nuclear translocation, and stabilized HIF\u20131\u03b1 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\u2013like mice. Conclusions: Taken together, evidence from these experimental models indicates that STEAP4 shapes oxidative stress and granulosa cell apoptosis by operating through the ROS\u2013TERT\u2013TP53 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.<\/jats:p>","DOI":"10.3390\/cells15131220","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T08:05:38Z","timestamp":1783325138000},"page":"1220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["STEAP4\u2013Mediated ROS\u2013TERT\u2013TP53 Signaling Promotes Granulosa Cell Dysfunction in Experimental Models of Polycystic Ovary Syndrome"],"prefix":"10.3390","volume":"15","author":[{"given":"Xinxin","family":"Quan","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejie","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongxiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lun","family":"Suo","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"},{"name":"Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-4401","authenticated-orcid":false,"given":"Qiuju","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Assisted 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