{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:06:53Z","timestamp":1791994013450,"version":"4.4.0"},"reference-count":110,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is closely associated with mitochondrial damage, diminished glutathione peroxidase 4 activity, dysfunction of the System Xc\n                    <jats:sup>\u2212<\/jats:sup>\n                    cystine\/glutamate antiporter, and disruptions in iron metabolism. Infections of the human reproductive system and associated reproductive disorders pose a significant global public health challenge, characterized by diverse pathogens and complex pathogenic mechanisms. Recent research has revealed that ferroptosis plays a critical role in the pathological processes of many of these infections. This review systematically elaborates on the central mechanistic role of ferroptosis in various pathologies of the reproductive system. These include CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell depletion and immunological non-response in Human Immunodeficiency Virus (HIV) infection, the development of Human Papillomavirus (HPV)-associated cervical cancer,\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    -induced endometritis and mastitis, as well as male infertility, pre-eclampsia, and ovarian cancer linked to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Despite the diversity of the pathogens, they can all trigger ferroptosis through common mechanisms, such as disrupting the Nrf2\/GPX4 antioxidant axis, impairing the System Xc\n                    <jats:sup>\u2212<\/jats:sup>\n                    \u2013GSH\u2013GPX4 pathway, and inducing dysregulation of iron metabolism. Furthermore, ferroptosis interacts intricately with pyroptosis and apoptosis, forming a complex network that collectively regulates the outcome of infections and the extent of tissue damage. Notably, ferroptosis plays a context-dependent dual role in various reproductive system infections. During the initial phases of infection, it exerts a protective effect by eliminating pathogens and curbing infection progression. In contrast, during advanced or chronic stages, ferroptosis exacerbates tissue injury and promotes disease pathogenesis. The ferroptosis pathway holds great therapeutic promise, either through inhibitors that safeguard host cells or inducers that eradicate drug-resistant bacteria by triggering a \u201cferroptosis-like\u201d state. Nevertheless, challenges remain for clinical translation, as the ferroptosis network is incompletely understood, and the tissue selectivity and long-term safety of targeted drugs are unverified. Future studies must elucidate host-pathogen interactions to develop precise targeted therapies.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1713074","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T06:43:08Z","timestamp":1765953788000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Ferroptosis in human reproductive tract infections and associated disorders: mechanisms and emerging therapeutic opportunities"],"prefix":"10.3389","volume":"16","author":[{"given":"Xinchen","family":"Wan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longyan","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhandi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengbo","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: an iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e52280","DOI":"10.15252\/embr.202052280","article-title":"PPAR\u03b1 alleviates iron overload-induced ferroptosis in mouse liver","volume":"23","author":"Xing","year":"2022","journal-title":"EMBO Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.molcel.2020.11.024","article-title":"Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1","volume":"81","author":"Yan","year":"2021","journal-title":"Mol Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1002\/jlb.4mr1019-189r","article-title":"Incomplete immune reconstitution in HIV\/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders","volume":"107","author":"Yang","year":"2020","journal-title":"J Leukoc Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104382","article-title":"Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4(+) T lymphocytes in HIV-infected immune non-responders","volume":"86","author":"Xiao","year":"2022","journal-title":"EBioMedicine"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2024.106151","article-title":"Transcriptomic crosstalk between viral and host factors drives aberrant homeostasis of T-cell proliferation and cell death in HIV-infected immunological non-responders","volume":"88","author":"Tang","year":"2024","journal-title":"J Infect"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102689","article-title":"HIV-1 Tat-mediated microglial ferroptosis involves the miR-204-ACSL4 signaling axis","volume":"62","author":"Kannan","year":"2023","journal-title":"Redox Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.3.835","article-title":"Levels of major selenoproteins in T cells decrease during HIV infection and low molecular mass selenium compounds increase","volume":"96","author":"Gladyshev","year":"1999","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1080\/13510002.2025.2546496","article-title":"Involvement of endolysosome iron in HIV-1 gp120-, morphine-, and iron supplementation-induced disruption of the reactive species interactome and induction of neurotoxicity","volume":"30","author":"Kumar","year":"2025","journal-title":"Redox Rep"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10101638","article-title":"Quercus acuta thunb. 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