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However, the pathogenesis remains mysterious, and therapeutic options are limited. The current study aimed to elucidate the molecular pathogenesis of OPF, thereby proposing a novel treatment protocol. In this study, single\u2010cell RNA sequencing analysis was conducted to identify the role of Piezo1 in the osteogenic capacity of LEPR<jats:sup>+<\/jats:sup> BMSCs in the healing process of fracture. Single\u2010cell trajectory analysis and pseudo\u2010time ordering were used to elucidate the differentiation trajectory of LEPR<jats:sup>+<\/jats:sup> BMSCs and Piezo1 expression. Molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTs) were performed to assess the interaction between Piezo1 and ASP. The ovariectomized (OVX) model combined with femoral bone fracture was utilized to evaluate the osteoprotective effect of ASP in\u00a0vivo. The alkaline phosphatase (ALP) assay and alizarin red S (ARS) staining were applied to evaluate the osteogenic differentiation potential of LEPR<jats:sup>+<\/jats:sup> BMSCs. The three\u2010dimensional culture was utilized to assess the proliferation and sphere\u2010forming ability of LEPR<jats:sup>+<\/jats:sup> BMSCs. The scratch wound healing and tube formation assay were employed to detect the angiogenesis of endothelial cells (ECs). Furthermore, western blotting, immunofluorescence staining, and flow cytometry assays were utilized to detect the relevant protein expression. Initially, single\u2010cell RNA sequencing analysis was utilized to identify Piezo1 as a key factor in osteogenic differentiation of LEPR<jats:sup>+<\/jats:sup> BMSCs during fracture healing. By molecular docking, CETSA, and DARTs analysis, Asperosaponin VI (ASP) was identified as a potentially effective monomer for Piezo1. Histologically, ASP enhanced the coupling of PODXL<jats:sup>+<\/jats:sup> ECs and LEPR<jats:sup>+<\/jats:sup> BMSCs within the callus of osteoporotic fractures. Notably, ASP improved LEPR<jats:sup>+<\/jats:sup> BMSCs' osteogenic potential and PODXL<jats:sup>+<\/jats:sup> ECs' angiogenesis. The augmented angiogenic capacity of PODXL<jats:sup>+<\/jats:sup> ECs was mediated by vascular endothelial growth factor (VEGF), an effect nullified by siPiezo1 in LEPR<jats:sup>+<\/jats:sup> BMSCs. Further, ASP significantly elevated P\u2010ERK1\/2, YAP, and VEGF expression, the downstream molecules of Piezo1 in the LEPR<jats:sup>+<\/jats:sup> BMSCs.This study initially revealed that the findings suggest that ASP may facilitate the coupling of LEPR<jats:sup>+<\/jats:sup> BMSCs and PODXL<jats:sup>+<\/jats:sup> ECs by activating the Piezo1\/ERK1\/2\/YAP\/VEGF signaling pathway in LEPR<jats:sup>+<\/jats:sup> BMSCs, thus indicating a promising therapeutic strategy for osteoporotic fracture management.<\/jats:p>","DOI":"10.1002\/ptr.8523","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T18:49:48Z","timestamp":1747766988000},"page":"3148-3166","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Asperosaponin VI Promotes Osteoporotic Fracture Healing by Targeting Piezo1 to Enhance the Coupling of LEPR<sup>+<\/sup> BMSCs and PODXL<sup>+<\/sup> ECs"],"prefix":"10.1002","volume":"39","author":[{"given":"Renchao","family":"Dong","sequence":"first","affiliation":[{"name":"Shandong Key Laboratory of Digital Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wei","sequence":"additional","affiliation":[{"name":"Shandong Key Laboratory of Digital Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Tian","sequence":"additional","affiliation":[{"name":"Shandong Key Laboratory of Digital Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Ma","sequence":"additional","affiliation":[{"name":"Shandong Key Laboratory of Digital Traditional Chinese Medicine Shandong University of 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