{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:33:01Z","timestamp":1791495181136,"version":"4.3.4"},"reference-count":60,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Recurrent vulvovaginal candidiasis (RVVC) is a chronic inflammatory disease primarily caused by Candida albicans (C. albicans). Its pathogenesis remains incompletely understood, and clinical management is challenged by recurrence and drug resistance. Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, has been implicated in various infectious and inflammatory diseases. However, its role in RVVC remains unclear, with a particular lack of evidence from clinical samples and animal experiments. Objective: This study aimed to investigate the association between RVVC and ferroptosis. First, we analyzed high-throughput sequencing data from human RVVC samples in the Gene Expression Omnibus (GEO) database to identify the expression profile of ferroptosis-related genes. Second, using an established murine model of chronic vulvovaginal candidiasis (CVVC), we validated changes in ferroptosis-related markers in vaginal tissues in vivo. Furthermore, an in vitro model of C. albicans-infected bone marrow-derived macrophages (BMDMs) was employed to explore the underlying mechanisms. This study provides experimental evidence for elucidating the pathogenesis of RVVC and exploring novel therapeutic strategies. Methods: The RVVC-related gene expression dataset GSE278036 was obtained from the GEO database. Differentially expressed genes (DEGs) were screened using the DESeq2 algorithm and intersected with ferroptosis-related genes from the FerrDb database to identify key targets. A protein\u2013protein interaction (PPI) network was constructed using the STRING database and Cytoscape software, and hub genes were identified via the Betweenness centrality algorithm. Functional and pathway analyses, including gene set enrichment analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and WikiPathways, were performed. Immune infiltration analysis characterized the immune microenvironment in RVVC patients. A CVVC mouse model was established in vivo, and a C. albicans-BMDMs infection model was established in vitro. The ferroptosis inhibitor ferrostatin-1 (Fer-1) was administered to investigate the pathological function and regulatory mechanisms of ferroptosis in RVVC at the molecular, cellular, and tissue levels. Results: Differential analysis identified 3132 DEGs in RVVC, which intersected with ferroptosis-related genes to yield 194 key targets. Among them, 20 hub genes were identified, including ferroptosis regulators and inflammatory factors. Functional enrichment analysis confirmed that these shared targets regulate RVVC pathology through a \u201cferroptosis-inflammation-immunity\u201d multi-pathway network. Immune infiltration analysis revealed a specific immune disorder in RVVC patients characterized by \u201cactivation of the pro-inflammatory innate immune axis and suppression of the adaptive immune axis,\u201d which was closely associated with ferroptosis-related genes. In vivo and in vitro experiments confirmed that C. albicans infection induced ferroptosis in vaginal tissues and macrophages, as manifested by lipid ROS accumulation, Fe2+ overload, GSH depletion, downregulation of GPX4 and SLC7A11, upregulation of ACSL4, 4-HNE, and MDA, and mitochondrial structural damage. Macrophages were identified as key target cells for ferroptosis, and their ferroptosis led to impaired antifungal function. Fer-1 treatment significantly inhibited ferroptosis, reduced vaginal histopathological damage and inflammatory cell infiltration, decreased fungal burden, downregulated abnormally elevated inflammatory factors, and restored Th1\/Th2 immune balance. Furthermore, Fer-1 preserved macrophage viability and enhanced their antifungal killing capacity. Conclusions: This study provides the first evidence linking RVVC to ferroptosis through a combination of clinical data analysis and experiments, suggesting that ferroptosis is involved in its pathological process. These findings offer a new perspective for elucidating RVVC pathogenesis and developing targeted therapeutic strategies.<\/jats:p>","DOI":"10.3390\/antiox15040407","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:07:13Z","timestamp":1774433233000},"page":"407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ferroptosis in Recurrent Vulvovaginal Candidiasis Through Integrated Bioinformatics and Experimental Validation"],"prefix":"10.3390","volume":"15","author":[{"given":"Yue-Min","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Xi \u2018an Jiaotong University, No.157 Siwu Road, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-9672","authenticated-orcid":false,"given":"Hui","family":"Yu","sequence":"additional","affiliation":[{"name":"Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"},{"name":"National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi \u2018an Jiaotong University, No.157 Siwu Road, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4367-8316","authenticated-orcid":false,"given":"Hao-Yan","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi \u2018an Jiaotong University, No.157 Siwu Road, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Meng","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi \u2018an Jiaotong University, No.157 Siwu Road, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Fang","family":"An","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi \u2018an Jiaotong University, No.157 Siwu Road, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e0004623","DOI":"10.1128\/mbio.00046-23","article-title":"Glycogen Metabolism in Candida albicans Impacts Fitness and Virulence during Vulvovaginal and Invasive Candidiasis","volume":"14","author":"Miao","year":"2023","journal-title":"mBio"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41541-025-01171-4","article-title":"Protective efficacy of the pan-fungal vaccine NXT-2 against vulvovaginal candidiasis in a murine model","volume":"10","author":"Wychrij","year":"2025","journal-title":"NPJ Vaccines"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sinoca, M., Maione, A., Gambino, E., Imparato, M., Galdiero, M., de Alteriis, E., Galdiero, E., and Guida, M. 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