Metformin alleviates paraquat-induced pulmonary fibrosis by promoting caveolin-1 and inhibiting ferroptosis.

No effective clinical therapeutic strategies are currently available for paraquat (PQ)-induced pulmonary fibrosis. This study determined whether metformin (MET) ameliorates PQ-induced pulmonary fibrosis and the epithelial-mesenchymal transition (EMT) in alveolar epithelial cells and explored the underlying molecular mechanisms. Expression of EMT-related markers, ferroptosis-related indicators, and caveolin-1 were examined and the regulatory role of the EZH2/H3K27me3 axis was evaluated using in vitro and in vivo models. PQ induced the EMT and ferroptosis in MLE-12 cells. MET upregulated caveolin-1 expression by inhibiting EZH2 and reducing H3K27me3, which in turn suppressed ferroptosis. MET attenuated PQ-induced pulmonary fibrosis via this signaling pathway and these results were further validated in animal models.