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Bone aging contributes to various age-related disorders, including periodontitis. Dental follicle stem cells (DFSCs) serve as ideal seed cells for periodontal regenerative therapy. Insulin-like growth factor binding protein 5 (IGFBP5) has been reported to exert complex and context-dependent effects. However, its role in DFSC senescence remains undefined. In this study, we observed a significant decrease in IGFBP5 expression in DFSCs undergoing replicative or H\u2082O\u2082-induced senescence. Functional experiments demonstrated that IGFBP5 overexpression alleviated cellular senescence and enhanced osteogenic potential, a process linked to the modulation of non-canonical Wnt signaling. WNT5B was then identified as a potential downstream regulator involved in mediating the pro-osteogenic effects of IGFBP5. To translate these findings clinically, we developed Gel-vHA@oe-DFSC, a nanoparticle-embedded hydrogel system for cell delivery, which enhanced the therapeutic efficacy of DFSCs and promoted periodontal regeneration in a rat model. Collectively, our study reveals a novel function of IGFBP5 in mitigating DFSC senescence and presents a promising strategy for combating periodontal bone loss.<\/jats:p>","DOI":"10.1038\/s41368-026-00463-2","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:01:43Z","timestamp":1789426903000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IGFBP5 alleviates periodontitis by reversing human dental follicle stem cell senescence via the non-canonical Wnt pathway"],"prefix":"10.1038","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8049-1732","authenticated-orcid":false,"given":"Yuru","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7953-1303","authenticated-orcid":false,"given":"Yue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3407-2778","authenticated-orcid":false,"given":"Yuguo","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5839-7114","authenticated-orcid":false,"given":"Weihua","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-3205","authenticated-orcid":false,"given":"Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"463_CR1","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1152\/physrev.00020.2018","volume":"99","author":"A Calcinotto","year":"2019","unstructured":"Calcinotto, A. et al. 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