Puerarin alleviates crystalline silica-induced pulmonary fibrosis by suppressing mtDNA leakage-induced senescence and EMT in alveolar type II cells

Silicosis, caused by inhalation of crystalline silica (SiO2), remains a serious and persistent public health concern. Puerarin (Pue), a bioactive isoflavone derived from Pueraria lobata, is known for its anti-inflammatory and antioxidant properties; however, its protective effects and underlying mechanisms in silicosis have not been fully elucidated. In this study, alveolar type II (AT2) cells and male C57BL/6 J mice were used to investigate the anti-aging and anti-fibrotic effects of Pue and Pue-enriched Pueraria lobata tea (Plt) in experimental silicosis. Transcriptomic and molecular analyses revealed that SiO2 exposure induced epithelial-mesenchymal transition (EMT) and cellular senescence in AT2 cells, accompanied by mitochondrial DNA (mtDNA) leakage into the cytoplasm and activation of the cGAS-STING signaling pathway. Pharmacological inhibition of mtDNA transcription and replication attenuated mtDNA leakage, thereby alleviating AT2 cell senescence and EMT. Notably, Pue significantly reduced senescence and EMT by suppressing mtDNA leakage in SiO2-exposed AT2 cells. Consistently, both Pue and Pue-enriched Plt ameliorated pulmonary aging and fibrosis in SiO2-inhaled C57BL/6 J mice. Collectively, these findings suggest that Pue and Plt alleviate SiO2-induced pulmonary fibrosis by mitigating mtDNA leakage-induced senescence and EMT, highlighting a potential preventive and interventional strategy based on natural bioactive compounds for SiO2-induced pulmonary fibrosis.