Inflammatory and extracellular matrix pathways in the association between heart failure and lung cancer risk

Aims Heart failure (HF) has been associated with an increased risk of incident lung cancer (LC), but the molecular mechanisms underlying this association beyond shared risk factors remain poorly characterised. This study aimed to investigate whether plasma protein-derived biological pathway activities are associated with mediation of the HF–LC association in a large, population-based cohort. Methods and results We conducted a retrospective analysis of 438,892 UK Biobank participants. Time-varying Cox proportional hazards models assessed the association between HF and incident LC. A sex-stratified multiple mediation analysis was performed in the proteomic subcohort ( n = 40,988), using pathway activity scores derived from 2,921 plasma proteins. Over a median follow-up of 13.1 years, HF was significantly associated with an increased risk of LC in both men (HR 1.32; 95% CI 1.11–1.56) and women (HR 1.39; 95% CI 1.09–1.76), with significant effect modification by sex ( P for interaction <0.001). In the prevalent-HF mediation cohort, inflammatory and extracellular matrix (ECM) remodelling pathways collectively accounted for 56.4% of the total effect in men and 41.1% in women. Key mediating pathways included collagen degradation and innate immune activation via Toll-like receptors in men, and inflammatory cytokine signalling and TNF receptor binding in women. Conclusion HF is associated with an increased risk of developing LC. This association is statistically consistent with mediation by systemic inflammatory and ECM remodelling pathways, with notable sex-specific differences. These findings support the hypothesis that HF is associated with a systemic milieu consistent with a pro-tumorigenic state, providing exploratory mechanistic insight into reverse cardio-oncology.