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Method: Sixty 4-week-old female ICR mice of the same batch number were selected and their systems were divided into 6 groups (n = 10): normal (Control, Ctrl) group, model (Polycystic Ovary Syndrome, PCOS) group, treatment (Vitexin, The Vit group, normal NR4A1 gene silencing group (Ctrl NR4A1-\/-), NR4A1 gene silencing model group (PCOS NR4A1-\/-), and NR4A1 gene silencing treatment group (Vit NR4A1-\/-). Silencing gene modeling was performed by tail vein injection of adeno-associated virus (serotype AAV-8), and the mouse genotypes were detected by qRT-PCR technology 14 days after injection. After the genotype was determined, the PCOS group and the PCOS NR4A1-\/- group were administered dehydroepandrosterone (6 mg\/100 g\/d) by gavage for 28 consecutive days for modeling, while the Vit group and the Vit NR4A1-\/- group were treated with dehydroepandrosterone + vitexin (10 mg\/kg\/d) by gavage for 28 consecutive days. All mice were raised with pure water and regular maintenance food. After 4 weeks of drug intervention, the mice were euthanized and samples were collected. The pathological changes in ovarian tissue were observed by H&amp;E staining, and the degree of ovarian tissue fibrosis was observed by Masson staining. The levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in mouse serum were detected by biochemical kits. The levels of inflammatory factors (IL-1\u03b2, IL-6, IL-18, TNF-\u03b1) in mouse serum were determined by enzyme-linked immunosorbent assay. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect oxidative kinase (Gsta4, Prdx3, Mgst1, Gpx3, Gsr), inflammatory factors (Nlrp3, Caspase-1, Asc, Il-1\u03b2, Il-18, Tnf-\u03b1) and fibrotic pathway-related genes (Tgf-\u03b21, Smad3, Collagen1, CTGF, \u03b1-SMA, Mmp-13, and \u03b2-catenin) in ovarian tissues. The levels of inflammatory factors (NLRP3, Caspase-1, ASC, IL-1\u03b2, IL-18, TNF-\u03b1, I\u03baB\u03b1) and fibrosis in mice were determined by Western blot method, and statistical description and analysis were performed using SPSS software. Result: In the wild-type genotype group, compared with the PCOS group, Vit treatment could effectively regulate the metabolic abnormalities of PCOS mice, including inhibiting excessive weight gain, restoring normal glucose tolerance, and reducing body fat content. After Vit treatment, the levels of MDA, TC, TG, LDL, IL-1\u03b2, IL-6, IL-18 and TNF-\u03b1 in the serum of PCOS mice were significantly reduced, while the levels of SOD and HDL in the serum of PCOS mice were increased. The staining results indicated that Vit treatment could significantly inhibit the process of ovarian fibrosis in PCOS mice. The results of WB and PCR demonstrated that after Vit gavage treatment in mice, inflammatory and fibrotic factors such as Nlrp3, Caspase-1, Asc, Il-1\u03b2, Il-18, Tgf-\u03b21, Smad3, Collagen1, CTGF, and \u03b1-SMA in ovarian tissues could be significantly down-regulated, and the fibrotic level of ovarian tissues could be reduced. Among the same measurement indicators, the silenced NR4A1 group showed a certain degree of increase compared with the wild genotype group, but there was no significant difference. Conclusions: Vit intervention can restore the sex hormone levels and follicular development in ovarian tissues of PCOS mice, regulate reproductive endocrine disorders and abnormal lipid metabolism levels, and regulate the expression of Collagen I, a-SMA and CTGF in the ovaries by inhibiting the NR4A1\/NLRP3 signaling pathway, thereby improving the ovarian fibrosis level of PCOS mice. It is suggested that it may play a key role in the treatment of PCOS and the prevention and delay of its long-term complications.<\/jats:p>","DOI":"10.3390\/metabo16050332","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T14:19:29Z","timestamp":1778854769000},"page":"332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic Investigation of Vitexin in Ameliorating Ovarian Fibrosis in PCOS Mice via the NR4A1\/NLRP3 Signaling Pathway"],"prefix":"10.3390","volume":"16","author":[{"given":"Haoran","family":"Sun","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China"},{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Guilin Medical University, Guilin 541199, China"},{"name":"Department of Pharmacology, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiejing","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China"},{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Guilin Medical University, Guilin 541199, China"},{"name":"Department of Pharmacology, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengxue","family":"Pan","sequence":"additional","affiliation":[{"name":"School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6269-5846","authenticated-orcid":false,"given":"Jia-Le","family":"Song","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Enviromental Exposureomics and Entire Lifecycle Health, Guilin 541101, China"},{"name":"Guangxi Colleges and Universities Key Laboratory of Medical Biotechnology and Translational Medicine, Guilin 541199, China"},{"name":"School of Laboratory Medicine and Biotechnology, Guilin Medical University, Guilin 541100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China"},{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Guilin Medical University, Guilin 541199, China"},{"name":"Department of Pharmacology, School of Pharmacy, Guilin Medical University, Guilin 541199, China"},{"name":"School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.fertnstert.2023.07.025","article-title":"Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome","volume":"120","author":"Teede","year":"2023","journal-title":"Fertil. 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