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Histological evidence suggests that the epithelial barrier and immune system around the implant are weaker than those around natural teeth. In transcriptomic aspects, compared to periodontitis and PI, the specific molecules and cell types involved in the pathogenesis of PI have not been fully established. In the current study, gingival tissue samples were collected from patients, and single\u2010cell RNA sequencing was used to analyze the heterogeneities of epithelial barriers, immune defenses, and related response molecules in soft tissues around natural teeth and implants. Our work supports that the disruption of the epithelial barrier around the implant was one of the causes of PI. The cell communication between epithelial cells and stromal cells was inhibited by the midkine (MDK)\u2010nucleolin (NCL) pathway. The breakdown of the defense structure of connective tissue aggravated the progress of PI. In\u00a0vitro evidence demonstrated MDK's functional role in stromal regeneration through overexpression experiments. These findings provide critical molecular insights into the pathogenesis of PI and offer a strong rationale for the development of early, targeted clinical interventions aimed at preserving epithelial integrity and restoring immune defense in peri\u2010implant soft tissues.<\/jats:p>","DOI":"10.1096\/fj.202601037r","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T18:24:51Z","timestamp":1786213491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single\u2010Cell Analysis Reveals the Soft Tissue Structure Heterogeneity Aggravates Peri\u2010Implantitis Through MDK Signaling"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9044-2897","authenticated-orcid":false,"given":"Yiling","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Stomatology Zhongshan Hospital, Fudan University  Shanghai 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