Cytoprotective role of resveratrol in cigarette smoke-induced pyroptosis through Nrf2 pathway activation

Resveratrol, a natural polyphenolic compound, has garnered increasing attention due to its antioxidant and anti-inflammatory properties. In this study, we investigated its protective role against cigarette smoke extract (CSE)-induced pyroptosis in human bronchial epithelial cell lines (BEAS-2B, 16HBE, and A549) and a chronic cigarette smoke (CS)-exposed mouse model. CS exposure is a major pathogenic factor in chronic obstructive pulmonary disease, primarily through promoting oxidative stress, inflammation, and pyroptotic cell death. Our results demonstrate that resveratrol enhances the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, upregulating downstream antioxidant enzymes such as HO-1 and NQO1. This activation mitigates oxidative stress and inhibits the activation of the TXNIP/NLRP3/caspase-1 inflammasome axis. In vitro, resveratrol reduced ROS accumulation and proinflammatory cytokine release in CSE-stimulated human bronchial epithelial cells. In vivo, resveratrol partially restored lung function and redox homeostasis in CS-exposed mice. Moreover, mechanistic analyses revealed that resveratrol upregulates miR-200a expression, which directly targets Keap1, thereby relieving its inhibition of Nrf2. These findings suggest that resveratrol alleviates CSE-induced pyroptosis by modulating the miR-200a/Keap1/Nrf2 axis and may serve as a potential therapeutic strategy for smoking-related airway diseases. However, additional clinical studies are necessary to confirm its efficacy.