{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:00:11Z","timestamp":1792800011813,"version":"4.5.0"},"reference-count":42,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82171634"],"award-info":[{"award-number":["82171634"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["31971068"],"award-info":[{"award-number":["31971068"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["7242085"],"award-info":[{"award-number":["7242085"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. The apoptosis of granulosa cells (GCs) is strongly associated with the impaired follicular development in PCOS. The underlying mechanisms, however, remain incompletely elucidated. A significant increase in circulating lactic acid, an anaerobic respiration product, has been detected in PCOS patients. Yet, alterations in local ovarian lactic acid levels and their impact on GCs remain unknown. Methods: PCOS mouse models were established via 20-day daily subcutaneous dehydroepiandrosterone (DHEA) injections. In vitro experiments utilized DHEA-treated KGN cells to mimic hyperandrogenic conditions. Circulating, ovarian, and cellular lactic acid concentrations were quantified. Intracellular and extracellular pH values were measured using BCECF-AM fluorescent probe and a blood gas analyzer, respectively. Apoptosis was assessed through both flow cytometry and TUNEL assay. The antioxidant N-acetylcysteine (NAC) was used to investigate its effects on lactic acid levels and the subsequent GC apoptosis. Results: High androgen levels caused mitochondrial damage, promoted anaerobic glycolysis and led to lactic acid accumulation, inducing decreased intracellular pH and thus apoptosis of GCs. The antioxidant NAC effectively alleviated oxidative stress, mitigated mitochondrial damage, and decreased lactic acid levels and apoptosis in KGN cells. In PCOS mice, NAC improved ovarian morphology, but it did not affect the estrous cycle of the mice. Conclusions: Hyperandrogenemia-induced mitochondrial dysfunction caused the accumulation of lactic acid and thus apoptosis of ovarian GCs in PCOS mice. NAC enhanced mitochondrial function, consequently decreasing lactic acid concentrations. These findings suggest novel therapeutic targets for PCOS.<\/jats:p>","DOI":"10.3390\/antiox14101235","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T06:06:32Z","timestamp":1760508392000},"page":"1235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Androgen-Induced Lactic Acid Accumulation Contributes to the Apoptosis of Ovarian Granulosa Cells in Polycystic Ovary Syndrome Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Bining","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liting","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Shanxi Medical University, No.56, Xinjian South Road, Yingze District, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengfei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haowen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youyou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1038\/s41591-025-03592-z","article-title":"Single-Cell Profiling of the Human Endometrium in Polycystic Ovary Syndrome","volume":"31","author":"Eriksson","year":"2025","journal-title":"Nat. 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