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Recent clinical evidence suggests that dental implant placement can effectively prevent such bone loss, yet the mechanisms remain elusive. In this study, combined multi-dataset screening pinpointed sorting nexin 5 (Snx5) as a potential regulator of mechanotransduction, whose expression was downregulated in early peri-implant bone remodeling zones following implant placement. Functional studies showed that loss of Snx5 abolished the additional osteogenic enhancement normally induced by mechanical stimulation. In vivo, Snx5 deficiency disrupted the mechanosensitive activation of LepR\n                    <jats:sup>+<\/jats:sup>\n                    MSCs and compromised implant-induced osteogenesis. Mechanistically, Snx5 facilitates the recycling of phosphorylated EGFR (p-EGFR) back to the plasma membrane to sustain EGFR signaling. Loss of Snx5 redirects EGFR trafficking toward late endosomes and lysosomal degradation, thereby weakening its signaling. These findings uncover a previously unrecognized role for Snx5 in mediating the osteogenic fate of peri-implant BMSCs in response to mechanical cues, expanding the functional repertoire of the Snx family. Collectively, these findings highlight Snx5 as a novel regulator of mechanosensitive bone remodeling and suggest that its downregulation may contribute to peri-implant bone adaptation. This study provides new insights into how the mechanical microenvironment regulates bone repair and highlights Snx5 as a promising molecular target for modulating skeletal mechano-responsiveness in clinical bone regeneration.\n                  <\/jats:p>","DOI":"10.1038\/s41368-025-00423-2","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:03:43Z","timestamp":1771545823000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Implantation awakens peri-implant osteogenic potential via Snx5-EGFR axis-mediated mechanical transduction"],"prefix":"10.1038","volume":"18","author":[{"given":"Xue","family":"Jiang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuteng","family":"Weng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanhuizhi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haicheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8230-8599","authenticated-orcid":false,"given":"Zuolin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"423_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s40729-020-00280-0","volume":"6","author":"LM S\u00e1ez-Alcaide","year":"2020","unstructured":"S\u00e1ez-Alcaide, L. 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