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Although the progesterone receptor modulator RU486 is effective for pain relief, its impact on lesion regression is limited, possibly due to apoptosis resistance and overexpression of PARP1 in endometriotic cells. This study aimed to evaluate the synergistic therapeutic efficacy of combining RU486 with the PARP inhibitor olaparib, focusing on reactivating p53\u2010dependent apoptosis in endometriotic lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Primary ectopic endometrial stromal cells (EESCs) were used to assess the effects of RU486 and olaparib on cytotoxicity, apoptosis, DNA damage, mitochondrial membrane potential, and cell migration. Mechanistic investigations included flow cytometry, western blotting, RT\u2010qPCR, immunofluorescence, and comet assays. A murine endometriosis model was established to evaluate in vivo lesion suppression, pain behaviour, hormone levels, and treatment safety following combination therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>RU486 and olaparib exhibited strong synergy at a 1:4 ratio, significantly enhancing apoptosis in EESCs by coactivating p53 through distinct mechanisms\u2014transcriptional up\u2010regulation by RU486 and posttranslational stabilization by olaparib. This synergy intensified Bax\/Bcl\u20102\u2010mediated mitochondrial dysfunction, caspase\u20103 activation, and PARP1 cleavage. In vivo, the combination therapy achieved a 77.5% lesion weight regression, significantly exceeding monotherapies, while maintaining robust analgesic effects. Histological and molecular analyses confirmed DNA damage and enhanced apoptosis in lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>The combination medication enhanced apoptotic sensitivity in endometriosis by restoring p53 activity through targeting hormonal signalling and DNA repair pathways. This strategy offered strong potential for clinical translation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70360","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T23:20:07Z","timestamp":1771456807000},"page":"2947-2968","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic RU486 and olaparib therapy enhances apoptosis in endometriosis by simultaneously targeting hormonal signalling and DNA repair"],"prefix":"10.1111","volume":"183","author":[{"given":"Yujie","family":"Peng","sequence":"first","affiliation":[{"name":"Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences Zhejiang University  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Women's Hospital Zhejiang University School of Medicine  Hangzhou 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