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Inter-individual variability plays a key role regarding genetic polymorphisms in xenobiotic\u2011metabolizing enzymes. In this study, we searched PubMed, Scopus and Web of Science (up to April 2026) for observational studies and meta\u2011analyses evaluating CYP1A1, CYP1B1, CYP2E1, GSTM1, GSTT1, GSTP1 and GSTM3 polymorphisms in OSCC and OPMDs. Twenty-one studies met the inclusion criteria. Data on exposures, genotypes and risk estimates were extracted and synthesized qualitatively. Most studies showed that GSTM1 and\/or GSTT1 null genotypes are associated with increased risk of OSCC, particularly in Asian cohorts with heavy tobacco and\/or betel quid exposure. CYP1A1 and CYP2E1 variants exhibited more heterogeneous results, but several studies indicated elevated risk in smokers, drinkers and betel quid users. Stronger effects consistently appeared in gene\u2013environment interaction models. Polymorphisms in Phase I and Phase II metabolizing enzymes, especially GSTM1\/GSTT1 null and selected CYP1A1\/CYP2E1 variants, modulate susceptibility to OSCC in exposed individuals, supporting their potential use in risk stratification and targeted prevention strategies.<\/jats:p>","DOI":"10.1007\/s12032-026-03428-x","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T09:53:42Z","timestamp":1791453222000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The impact of genetic polymorphisms in xenobiotic-metabolizing enzymes and the risk of oral cancer: a critical review"],"prefix":"10.1007","volume":"43","author":[{"given":"Gabriel Carvalhal","family":"de Aguiar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Vitor","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"dos Anjos Ros\u00e1rio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorrany","family":"da Silva Avanci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rogerio Aparecido","family":"Dedivitis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Araki","family":"Ribeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"issue":"4\u20135","key":"3428_CR1","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.oraloncology.2008.06.002","volume":"45","author":"S Warnakulasuriya","year":"2009","unstructured":"Warnakulasuriya S. 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