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Accordingly, this study identified a positive association between FAP levels and periodontitis susceptibility using Mendelian randomization analysis. Human and mouse periodontitis tissues show elevated FAP and reduced osteolectin (OLN), an endogenous FAP inhibitor, indicating a FAP\/OLN imbalance. Single\u2010cell RNA sequencing revealed gingival fibroblasts (GFs) as the primary FAP and OLN source, with periodontitis\u2010associated GFs showing increased reactive oxygen species, cellular senescence, and mTOR pathway activation. Rapamycin treatment restored the FAP\/OLN balance in GFs. Recombinant FAP increased pro\u2010inflammatory cytokine secretion and osteoclast differentiation in macrophages, exacerbating periodontal damage, whereas FAP inhibition reduced macrophage inflammation, collagen degradation, and bone resorption in experimental periodontitis. Therefore, senescent fibroblasts drive the FAP\/OLN imbalance through mTOR activation, contributing to periodontitis progression. Consequently, targeting FAP may offer a promising therapeutic strategy for periodontitis.<\/jats:p>","DOI":"10.1002\/advs.202409398","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T03:06:07Z","timestamp":1735009567000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Senescent Fibroblasts Drive FAP\/OLN Imbalance Through mTOR Signaling to Exacerbate Inflammation and Bone Resorption in Periodontitis"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8541-2852","authenticated-orcid":false,"given":"Chenghu","family":"Yin","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan 430079 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangliang","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan 430079 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuling","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan 430079 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youde","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Stomatology Center The People's Hospital of Baoan Shenzhen (The Second Affiliated Hospital of Shenzhen University)  Shenzhen Guangdong 518081 P. 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