Obesity increases the risk of radiation-induced interstitial lung disease in lung cancer patients: Evidence for a renin-mediated mechanism

Background Obesity is a serious public health challenge known to adversely affect cancer outcomes, but its relationship with radiation-induced interstitial lung disease (RILD) in lung cancer patients is poorly investigated. Objectives This study aims to investigate the impact of obesity on RILD and identify key mediating factors. Design A multi-cohort clinical and mechanistic study. Methods A retrospective cohort (N=169) and a prospective cohort (N=87) of lung cancer patients treated between November 2018 and June 2025 were analyzed. Kaplan-Meier curves were used to estimate time to ≥ grade 2 RILD, overall survival (OS), and progression-free survival (PFS). A two-step Mendelian randomization (MR) analysis explored the mechanism by which obesity influences ILD through renin, further validated by enzyme-linked immunosorbent assay (ELISA). Results In the retrospective training cohort, overweight and obesity were associated with a higher risk of ≥ grade 2 RILD versus normal weight ( P = 0.002), with a similar trend in the prospective validation cohort ( P = 0.017). Furthermore, renin levels were higher in obesity than normal weight ( P < 0.001) and correlated with RILD grade (R = 0.670, P < 0.001). Finally, the two-step MR supported a causal effect of higher BMI on ILD (OR = 1.483, P < 0.001), partially mediated by renin (mediated proportion = 9.9%, P = 0.040). Conclusion Obesity is associated with ≥ grade 2 RILD in lung cancer patients through renin-mediated mechanisms in this study. These findings underscore the importance of risk stratification for patients with obesity and highlight renin as a potential therapeutic target for preventing and treating RILD.