{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:05:34Z","timestamp":1792785934274,"version":"4.5.0"},"reference-count":276,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82125014"],"award-info":[{"award-number":["82125014"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key Research and Developmental Program of China","award":["2024YFC2706902"],"award-info":[{"award-number":["2024YFC2706902"]}]},{"name":"National Key Research and Developmental Program of China","award":["2022YFA1103603"],"award-info":[{"award-number":["2022YFA1103603"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82421004"],"award-info":[{"award-number":["82421004"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371679"],"award-info":[{"award-number":["82371679"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32588201"],"award-info":[{"award-number":["32588201"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Distinguished Scholars of Shandong Province","award":["ZR2025QA12"],"award-info":[{"award-number":["ZR2025QA12"]}]},{"name":"Postdoctoral Science Foundation of China","award":["2026M792389"],"award-info":[{"award-number":["2026M792389"]}]},{"name":"Mingcheng Innovation Postdoctoral Research Foundation"},{"name":"Gusu School, Nanjing Medical University","award":["GSBSHKY202401"],"award-info":[{"award-number":["GSBSHKY202401"]}],"id":[{"id":"https:\/\/ror.org\/059gcgy73","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"Abstract<\/jats:title>\n \n BACKGROUND<\/jats:title>\n Ovarian aging is among the earliest functional declines in humans and acts as a pacemaker of female aging. It encompasses both physiological age-related ovarian decline and pathological accelerated aging, exemplified by premature ovarian insufficiency (POI). Increasing evidence positions the immune system as both a regulator of ovarian homeostasis and a driver of ovarian dysfunction. Age-related immunosenescence and chronic low-grade inflammation (inflammaging) coordinately drive ovarian aging through bidirectional crosstalk between systemic immunity and the ovarian immune microenvironment. POI frequently coexists with autoimmune disorders, reinforcing the central role of the immune-ovarian axis in reproductive aging. Elucidating this interplay may enable targeted immunomodulatory strategies to preserve reproductive longevity and mitigate systemic consequences of ovarian decline.<\/jats:p>\n <\/jats:sec>\n \n OBJECTIVE AND RATIONALE<\/jats:title>\n The aim was to synthesize current evidence on (i) immune regulation of normal ovarian physiology; (ii) immune alterations in physiological ovarian aging, including systemic immunosenescence and ovarian immune microenvironment remodelling; (iii) autoimmune dysregulation in POI; and (iv) the translational potential of immunomodulatory interventions for mitigating ovarian aging.<\/jats:p>\n <\/jats:sec>\n \n SEARCH METHODS<\/jats:title>\n Original articles published up to April 2026 were identified through PubMed using combinations of the terms \u2018immune system\u2019, \u2018ovarian function\u2019, \u2018inflammation\u2019, \u2018immune cell\u2019, \u2018ovarian aging\u2019, \u2018menopause\u2019, \u2018primary ovarian insufficiency\u2019, and \u2018therapeutics\u2019.<\/jats:p>\n <\/jats:sec>\n \n OUTCOMES<\/jats:title>\n Immune cells and cytokine networks form a specialized regulatory axis that governs folliculogenesis, ovulation, and luteal dynamics. This review synthesizes emerging evidence showing that this immune\u2013ovary axis undergoes profound remodelling during reproductive aging and that immune dysregulation is a causal driver of ovarian functional decline. Systemically, the menopausal transition accelerates immunosenescence and amplifies pro-inflammatory cytokine production. Locally, the aging ovary exhibits chronic inflammation, NLRP3 inflammasome activation, and accumulation of senescent cells with a senescence\u2011associated secretory phenotype. These changes coincide with a shift from tissue\u2011resident to monocyte\u2011derived macrophages and expansion of inflammatory \u03b3\u03b4 and double\u2011negative T cells. This progressive loss of immune homeostasis promotes follicular depletion, stromal fibrosis, and impaired steroidogenesis. POI represents a pathological extreme of this axis, characterized by autoimmune comorbidities, B cell-driven humoural abnormalities, T cell dysregulation, and genetic variants affecting immune pathways. Comparative analysis reveals both conserved inflammatory signatures shared with physiological aging and POI-specific immune features that reflect overt immune-mediated ovarian injury. By integrating systemic, local, and disease-specific immune mechanisms, this review reframes ovarian aging as a modifiable immunological process. Therapeutically, emerging immunomodulatory strategies range from molecular agents targeting inflammatory mediators and senescence programs, through cell-based immune reprogramming with stem cells, regulatory T cells, and senolytic immune effectors, to lifestyle-driven systemic immunomodulation. These strategies show promise in restoring ovarian immune homeostasis and extending the reproductive lifespan, with several of these approaches now advancing toward early-phase clinical evaluation.<\/jats:p>\n <\/jats:sec>\n \n WIDER IMPLICATIONS<\/jats:title>\n Collectively, the current evidence positions immune dysregulation as a mechanistic driver, rather than a secondary correlate, of ovarian aging. Integrating immune biomarkers into predictive frameworks and designing stratified immunomodulatory trials may shift ovarian aging management from symptomatic hormone replacement toward mechanism-based intervention. Reframing ovarian aging as a modifiable immune-mediated process offers new opportunities to extend female reproductive longevity and the female health span.<\/jats:p>\n <\/jats:sec>\n \n REGISTRATION NUMBER<\/jats:title>\n N\/A<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/humupd\/dmag030","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:46:03Z","timestamp":1789127163000},"source":"Crossref","is-referenced-by-count":0,"title":["Decoding the immune regulation of ovarian aging: mechanisms and therapeutic strategies"],"prefix":"10.1093","author":[{"given":"Changjing","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University , Jinan, Shandong,","place":["China"]},{"name":"National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University , Jinan, Shandong,","place":["China"]},{"name":"Key Laboratory of Reproductive Endocrinology, Shandong University, Ministry of Education , Jinan, Shandong,","place":["China"]},{"name":"Shandong Technology Innovation Center for Reproductive Health , Jinan, Shandong,","place":["China"]},{"name":"Shandong Provincial Clinical Research Center for Reproductive Health , Jinan, Shandong,","place":["China"]},{"name":"Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention , Jinan, Shandong,","place":["China"]},{"name":"Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No.2021RU001) , Jinan, Shandong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nianyu","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University , 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