The association between periodontal disease and lung cancer: a re-evaluation of independent causal relationships in the presence of smoking as a confounder and an exploration of potential mechanisms.

Periodontal disease and lung cancer are major global health burdens, and epidemiological evidence suggests a potential association between them. However, whether this relationship is independent of smoking-a strong common risk factor-remains controversial. This review systematically summarizes current evidence on the association, with emphasis on smoking confounding and underlying biological mechanisms. Meta-analyses consistently show a significant positive association, with adjusted hazard ratios ranging from 1.24 to 1.71 and dose-response relationships across disease severity and tooth loss. After rigorous statistical adjustment for smoking, most large cohort studies still show a robust association, though findings in never-smokers are inconsistent, suggesting possible residual confounding. Mechanistically, the "oral-lung axis" links periodontitis to lung carcinogenesis via three pathways: microbial translocation of pathogens such as Fusobacterium nucleatum, chronic inflammation-driven immune dysregulation involving Treg and IL-6, and epigenetic modifications including shared DNA methylation sites. Smoking may also act synergistically with periodontitis to amplify carcinogenic risk. Future research should prioritize precisely quantified smoking exposure, formal interaction analyses, and longitudinal multi-omics studies to support causal inference. This review provides a theoretical foundation for incorporating oral health assessment into lung cancer prevention strategies.