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Hyperoside, a bioactive flavonoid from Hypericum perforatum, exhibits therapeutic potential against URSA, yet its underlying mechanism of action remains unknown. In this study, we employed an integrated multi\u2010omics approach coupled with a multi\u2010dimensional validation framework that spanned URSA patient decidual tissues, in vivo mouse models, and in vitro telomerase\u2010immortalized human endometrial stromal cell (T\u2010hESC) decidualization system, to systematically investigate hyperoside's mechanism in URSA, with a focus on R\u2010loop\u2010driven endometrial stromal cell senescence. We found that hyperoside dose\u2010dependently reduced embryo resorption and rescued decidualization deficiency by preventing stromal cell senescence. Mechanistically, hyperoside effectively alleviated aberrant intracellular R\u2010loop accumulation, thereby suppressing excessive activation of the cyclic GMP\u2010AMP synthase\u2010stimulator of interferon genes (cGAS\u2010STING) pathway which contributes to the initiation of the cellular senescence program. Further target identification and validation experiments confirmed that DExH\u2010box helicase 9 (DHX9) was the functional molecular target of hyperoside, with the Thr419 residue serving as the critical binding site. Functional validation revealed that DHX9 knockdown or introduction of the T419A point mutation markedly attenuated the anti\u2010senescence and pro\u2010decidualization effects of hyperoside. In vivo experiments further confirmed that uterine\u2010specific knockdown of DHX9 reduced hyperoside's protective effects against R\u2010loop accumulation, cGAS\u2010STING pathway activation, and embryo loss. Collectively, these findings demonstrate that hyperoside alleviates stromal cell senescence and decidualization deficiency in URSA through DHX9\u2010dependent resolution of R\u2010loops and subsequent suppression of cGAS\u2010STING\u2010associated senescence signaling. More broadly, this work identifies R\u2010loop\u2010mediated genomic stress as a previously underappreciated contributor to URSA\u2010associated decidual dysfunction and provides a mechanistic basis for the protective effects of hyperoside through DHX9\u2010dependent R\u2010loop homeostasis.<\/jats:p>","DOI":"10.1002\/imt2.70150","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:48:14Z","timestamp":1784011694000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hyperoside alleviates endometrial stromal cell senescence in unexplained recurrent spontaneous abortion via DHX9\u2010mediated R\u2010loop resolution"],"prefix":"10.1002","volume":"5","author":[{"given":"Yuepeng","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Traditional Chinese Medicine (TCM) Gynecology Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University Hangzhou 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