{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:11:07Z","timestamp":1788844267014,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005270","name":"Fujian Provincial Department of Science and Technology","doi-asserted-by":"crossref","award":["2022J01172"],"award-info":[{"award-number":["2022J01172"]}],"id":[{"id":"10.13039\/501100005270","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005270","name":"Fujian Provincial Department of Science and Technology","doi-asserted-by":"crossref","award":["2024J01458"],"award-info":[{"award-number":["2024J01458"]}],"id":[{"id":"10.13039\/501100005270","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2022J01172"],"award-info":[{"award-number":["2022J01172"]}],"id":[{"id":"https:\/\/ror.org\/00rgzpv08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2024J01458"],"award-info":[{"award-number":["2024J01458"]}],"id":[{"id":"https:\/\/ror.org\/00rgzpv08","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Key Projects of Scientific and Technological Innovation in Fujian Province","award":["2022G028"],"award-info":[{"award-number":["2022G028"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>3-Nitropropionic acid (3-NPA) is an irreversible inhibitor of succinate dehydrogenase (SDH; mitochondrial complex II) that is widely used to model mitochondrial metabolic stress. Direct reproductive studies now show that 3-NPA can increase ovarian oxidative stress, granulosa-cell apoptosis, follicular atresia, alter ovarian reserve, impair oocyte maturation, and reduce fertility in experimental models. However, no ovarian study has yet demonstrated the complete succinate\u2013HIF-1\u03b1\u2013NLRP3 cascade proposed here. We therefore propose a testable framework in which SDH inhibition causes succinate accumulation and impaired respiratory electron flux, while redox stress provides an additional signal for HIF-1\u03b1 stabilization and NLRP3 activation. Succinate-mediated inhibition of prolyl hydroxylases provides a mechanistic route to HIF-1\u03b1 stabilization under normoxic or near-normoxic conditions, whereas NLRP3 activation may integrate mitochondrial danger signals with inflammatory signaling. Importantly, HIF-1\u03b1 is not intrinsically pathogenic in the ovary: physiological HIF-1\u03b1 signaling supports angiogenesis, ovulation, granulosa-cell survival, autophagy, and luteal remodeling, whereas persistent or excessive activation may become maladaptive. We further refine the proposed metabolic\u2013inflammatory threshold as a measurable state in which combined succinate\/redox burden and inflammasome activation exceed the adaptive capacity of a follicular unit. The model predicts that time-resolved measurements of succinate, SDH activity, HIF-1\u03b1 stabilization, NLRP3 activation, and follicular outcomes should reveal ordered relationships that can be tested by pharmacological and genetic intervention. This review distinguishes direct ovarian evidence from cross-system mechanistic evidence and identifies the experiments required to establish causality.<\/jats:p>","DOI":"10.3390\/biology15171557","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1557","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Succinate\u2013HIF-1\u03b1\u2013NLRP3 Axis in 3-Nitropropionic Acid-Induced Ovarian Dysfunction: A Testable Metabolic\u2013Inflammatory Framework"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4309-0221","authenticated-orcid":false,"given":"Zhenghong","family":"Zhang","sequence":"first","affiliation":[{"name":"Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou 350007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Defan","family":"Wang","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen 361102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghe","family":"Lin","sequence":"additional","affiliation":[{"name":"Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou 350007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingting","family":"Guo","sequence":"additional","affiliation":[{"name":"Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou 350007, China"},{"name":"College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7439-9630","authenticated-orcid":false,"given":"Zhengchao","family":"Wang","sequence":"additional","affiliation":[{"name":"Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou 350007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1095\/biolreprod.115.133652","article-title":"How is the number of primordial follicles in the ovarian reserve established?","volume":"93","author":"Findlay","year":"2015","journal-title":"Biol. 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