{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T05:59:33Z","timestamp":1781243973080,"version":"3.54.1"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"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. Cell Dev. Biol."],"abstract":"<jats:p>Female reproductive tissues repeatedly undergo controlled inflammation, immune adaptation, and tissue repair. Interleukin-33 (IL-33) and its receptor suppression of tumorigenicity 2 (ST2) sit at the center of these processes, but their roles in reproductive disease have often appeared contradictory. In this review, we integrate current evidence and propose that IL-33\/ST2 signaling is not simply pro-inflammatory or anti-inflammatory. Instead, it functions as a context- and stage-dependent regulatory axis shaped by hormonal status, tissue niche, cellular targets, and disease microenvironment. Under physiological conditions, properly timed and locally restricted IL-33\/ST2 activity supports ovarian tissue clearance, decidualization, embryo implantation, pregnancy maintenance, and repair. When this regulation is disrupted, the same pathway may contribute to chronic inflammation, fibrosis, immune imbalance, and reproductive dysfunction. Evidence is strongest in endometriosis and recurrent miscarriage, where experimental and mechanistic studies link IL-33\/ST2 to lesion inflammation, fibrosis, ILC2 and macrophage responses, uterine receptivity, and maternal\u2013fetal immune tolerance. In contrast, evidence in primary ovarian insufficiency and polycystic ovary syndrome remains mainly associative, involving altered serum or follicular-fluid IL-33\/ST2-related markers and inflammatory-metabolic phenotypes. This evidence hierarchy argues against interpreting IL-33 as a static biomarker or a uniformly harmful mediator. Future studies should define the temporal dynamics, cellular sources, and tissue-specific targets of IL-33\/ST2 signaling. Therapeutic development should prioritize precise, stage-specific, and cell-selective modulation rather than indiscriminate systemic blockade.<\/jats:p>","DOI":"10.3389\/fcell.2026.1808099","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T05:45:05Z","timestamp":1781243105000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The role of IL-33\/ST2 signaling in female reproductive diseases"],"prefix":"10.3389","volume":"14","author":[{"given":"Ningzhen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoxing","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Guangdong Women and Children Hospital","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingwei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.32007\/jfacmedbagdad.561443","article-title":"Interleukin\u201333, oxidative stress in prediabetic polycystic ovary syndrome patients with insulin resistance","volume":"56","author":"Al-Taie","year":"2014","journal-title":"J. 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