Renin-angiotensin system imbalance is associated with immunometabolic reprogramming and tissue repair in COPD-lung cancer comorbidity

Background Chronic obstructive pulmonary disease (COPD) and lung cancer frequently co-occur with shared inflammatory and metabolic drivers, while the systemic role of the renin-angiotensin system (RAS) in this comorbidity remains poorly understood. Methods We integrated Global Burden of Disease, Mendelian randomization, pan-cancer/single-cell transcriptomics, NHANES population data, and functional experiments to dissect this comorbidity, with mechanistic modeling to evaluate lifestyle factors and osteopontin's role in bone marrow mesenchymal stem cell (BMSC) retention and anti-inflammatory signaling. Results GBD analysis demonstrated socioeconomic patterning of COPD-lung cancer burden. Convergent multi-level evidence identified RAS imbalance as a key upstream regulator: the pro-inflammatory ACE/angiotensin II axis was activated while the protective ACE2/angiotensin-(1–7) axis was suppressed, driving immunometabolic reprograming, checkpoint activation, and Th17 inflammation, with coordinated epithelial, immune, and stromal alterations at single-cell resolution. Osteopontin acted as a downstream mediator, promoting BMSC retention via CD44/integrin β 1 interactions and modulating inflammation through PI3K/Akt signaling. Physical activity correlated with balanced RAS activity and lower disease risk. Conclusions We define a RAS–Th17/osteopontin axis as a central regulator of immunometabolic reprograming and tissue repair in COPD-lung cancer comorbidity. These findings support integrated therapeutic strategies targeting RAS, immunometabolism, and BMSC-based repair.