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Periodontitis is a common chronic inflammatory disease characterized by the progressive destruction of tooth-supporting structures. While periodontitis Has been associated with an increased risk of OSCC in epidemiological and mechanistic studies, the strength of this association is unclear. This systematic review and meta-analysis aimed to clarify this relationship by synthesizing current evidence, including potential biological mechanisms. A comprehensive search strategy was implemented across five databases to identify relevant publications up to June 2025. Eligible studies had human,\n                    <jats:italic>in vitro<\/jats:italic>\n                    , or animal data that evaluated the association between periodontitis and OSCC. A meta-analysis was conducted to assess the association between periodontitis and OSCC. From 6,992 records identified, 116 studies were included in the systematic review, and 26 were eligible for meta-analysis. The meta-analysis supports an association between both clinically assessed and self-reported periodontitis and an increased risk of OSCC, with similar associations observed for HNSCC overall. These clinical associations are supported by experimental evidence demonstrating that key periodontal pathogens, such as\n                    <jats:italic>Porphyromonas gingivalis<\/jats:italic>\n                    and\n                    <jats:italic>Fusobacterium nucleatum<\/jats:italic>\n                    , contribute to OSCC progression through mechanisms involving inflammation, epithelial-to-mesenchymal transition (EMT), and immune evasion. In conclusion, although epidemiological and mechanistic studies discussed in this review provide evidence of an association between periodontitis and OSCC, future studies using standardized diagnostic criteria, robust design, and clinically relevant experimental models are essential for causal inferences and to deepen knowledge of underlying mechanisms.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    Summary graphic of the methodology and analysis of a systematic review on periodontitis and oral cancer, based on cohort, case-control, animal and\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies. It highlights the observed associations, with recommendations for standardization of methodology in future studies and a summary of knowledge gaps.\n                  <\/jats:p>","DOI":"10.1007\/s10555-025-10285-z","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:01:08Z","timestamp":1757430068000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Demystifying the link between periodontitis and oral cancer: a systematic review integrating clinical, pre-clinical, and in vitro data"],"prefix":"10.1007","volume":"44","author":[{"given":"Suzane C.","family":"Pigossi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jov\u00e2nia A.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcell C.","family":"de Medeiros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9lio F. 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