Hydrogen sulfide attenuates PM2.5-induced COPD by inhibiting cellular senescence via the Klotho/Parkin-mediated mitophagy signaling pathway.

Fine particulate matter (PM2.5), an atmospheric pollutant, plays a crucial role in mediating the occurrence of chronic obstructive pulmonary disease (COPD). Hydrogen sulfide (H2S) has shown therapeutic potential in countering COPD, but the underlying mechanisms remain elusive. This study aimed to elucidate the potential mechanisms of H2S in inhibiting cellular senescence and combating the progression of COPD. In this study, mouse and cell models were initially established by pretreating with PM, PM2.5, and NaHS. It was showed that increased expressions of p16, p21, and β-gal positive cells, along with elevated inflammatory and oxidative stress markers and reduced antioxidant markers, could be observed in COPD patients as well as in PM2.5-induced cell and mouse models, correlating with decreased endogenous H2S levels. Pre-treatment with NaHS reversed these effects, enhancing Klotho expression, inhibiting IGF-1R, and activating the Parkin- dependent mitophagy pathway, which significantly mitigated airway inflammation and emphysema. Klotho silencing in BEAS-2B cells exacerbated the PM2.5-induced damage and diminished the protective effects of NaHS, confirming the link between Klotho and the downstream Parkin-dependent mitophagy pathway. Our findings suggest that H2S mitigates PM2.5-induced senescence in airway epithelial cells by modulating the Klotho/IGF-1R/Parkin-dependent mitophagy pathway, thereby alleviating airway inflammation and emphysema. This provides a foundation for devising innovative treatment approaches for COPD and mitigating the health effects of atmospheric pollution.