Human Turbinate Mesenchymal Stromal Cell-Derived Exosomes Alleviate PM2.5-Induced Pyroptosis via Promoting Mitophagy in Human Vocal Fold Fibroblasts.

Chronic laryngitis is a persistent inflammatory disorder that has recently been linked to air pollution. Fine particulate matter (PM2.5) is a major air pollutant capable of inducing pyroptosis, a caspase-1-dependent inflammatory form of programmed cell death characterized by gasdermin D cleavage, plasma membrane rupture, and the release of proinflammatory cytokines. However, the mechanisms underlying PM2.5-induced pyroptosis in the larynx and the potential therapeutic strategies remain unclear. In this study, we investigated the protective effects of human turbinate mesenchymal stromal cell-derived exosomes (hTMSC-exos) on PM2.5-induced pyroptosis in human vocal fold fibroblasts (hVFFs). PM2.5 exposure triggered pyroptotic cell death, as evidenced by increased LDH release, PI positivity, GSDMD-N expression, and IL-1β and IL-18 secretion. It also induced excessive reactive oxygen species (ROS) production, disrupted mitochondrial function, and impaired mitophagy, as indicated by p62 accumulation and suppressed PINK1/Parkin expression. Treatment with hTMSC-exos significantly alleviated these effects, reducing pyroptosis markers, lowering ROS production, and preserving mitochondrial membrane potential. Mechanistically, hTMSC-exos restored mitophagy activity suppressed by PM2.5, as demonstrated by increased LC3-II, PINK1, and Parkin expression and decreased p62 levels. Fluorescence imaging further confirmed enhanced co-localization of mitochondria with LC3-II. Importantly, the protective effects of hTMSC-exos were abolished by the mitophagy-specific inhibitor cyclosporin A, confirming that mitophagy activation is essential for exosome-mediated protection. These findings suggest that hTMSC-exos attenuate PM2.5-induced pyroptosis through a mitophagy-dependent mechanism, providing new insight into the pathogenesis of environmentally induced laryngeal injury and highlighting the therapeutic potential of exosome-based approaches for chronic laryngitis.