Resveratrol attenuates oxidative stress in chronic obstructive pulmonary disease by Nrf2-mediated inhibition of ferroptosis.
Abstract
Background
Oxidative stress and ferroptosis contribute to cigarette smoke (CS)-related epithelial injury in chronic obstructive pulmonary disease (COPD), but the extent to which resveratrol (RES) modulates this process through Nrf2 remains incompletely defined.
Methods
We used a CS plus lipopolysaccharide-induced mouse model and CSE-stimulated BEAS-2B cells. Lung histopathology, BALF inflammation, oxidative stress indices, ferroptosis-related markers, C11-BODIPY lipid peroxidation, Nrf2/HO-1 signaling, and public COPD transcriptomic data were analyzed. ML385 was applied to pharmacologically inhibit Nrf2 in vitro.
Results
RES attenuated lung injury and inflammatory infiltration, restored GSH, and reduced MDA, Fe2 + , and 4-HNE accumulation. RES also decreased ferroptosis-associated gene expression and restored Nrf2, HO-1, GPX4, and SLC7A11 expression. In BEAS-2B cells, RES improved viability and reduced lipid peroxidation after CSE exposure, whereas ML385 partially reversed these effects. Transcriptomic analysis supported enhanced oxidative stress/ferroptosis activity and altered Nrf2-related signaling in COPD samples.
Conclusion
RES mitigates COPD-related oxidative stress and ferroptosis, at least partly through Nrf2-associated antioxidant signaling. These findings support further investigation of the Nrf2-ferroptosis network as a therapeutically relevant pathway in COPD.