Dietary inflammatory index and lung cancer risk: multi-cohort evidence and plasma proteomic profiles

Accumulating evidence links dietary inflammatory potential to cancer, yet its association with lung cancer incidence and mortality remains inconsistent. This study aimed to examine the relationship between the Dietary Inflammatory Index (DII) and lung cancer risk, and to explore the underlying molecular mechanisms.

Associations between DII scores and lung cancer incidence were evaluated using Cox proportional hazards models within the UK Biobank cohort, with external validation performed in the NHANES dataset. Mediation analyses were conducted to investigate plasma proteins as potential mediators. Subsequent analyses included functional enrichment assessment, protein-protein interaction network mapping, and Mendelian randomization to characterize candidate proteins and ascertain the causal effects of specific dietary components.

During a median follow-up of 11.8 years among 198,735 participants, 1,024 lung cancer cases were identified. Elevated DII scores demonstrated a J-shaped nonlinear positive association with lung cancer risk (Q4 vs Q1 HR 1.30, 95% CI 1.08-1.56). Proteomic screening revealed 133 candidate proteins enriched in immune regulation and inflammatory signaling pathways, with IL-6 identified as a central hub. Thirteen proteins partially mediated the association between DII and lung cancer risk, with HGF and PRSS8 each accounting for approximately 25% or more of the total effect. HGF, TNFSF13B, and LGMN were characterized as potential drug-targetable mediators.

Pro-inflammatory dietary patterns were associated with increased lung cancer risk alongside alterations in circulating protein profiles. These findings provide potential mechanistic insights into the role of dietary inflammation in lung carcinogenesis and underscore the preventive potential of anti-inflammatory dietary interventions.