Epigenetic silencing of SOD2 exacerbates mitochondrial oxidative stress and promotes pulmonary fibrosis.

Mitochondrial oxidative damage-mediated dysfunction is implicated in pulmonary pathogenesis, yet the molecular mechanisms linking redox imbalance to pulmonary fibrosis remain elusive. In this study, we demonstrate that DNA methyltransferase 3 A (DNMT3A) drives fibroblast activation and pulmonary fibrosis by epigenetically repressing superoxide dismutase 2 (SOD2), a critical antioxidant enzyme. Using fibroblast-specific DNMT3A-deficient mice and bleomycin-induced pulmonary fibrosis models, we observed that DNMT3A ablation significantly attenuated mitochondrial oxidant overproduction, restored mitochondrial membrane potential (MMP), and reduced fibrotic progression. Mechanistically, DNMT3A directly bound to the SOD2 promoter, inducing hypermethylation and transcriptional silencing, which exacerbated oxidative stress and fibroblast proliferation. Conversely, AAV6-mediated SOD2 overexpression or DNMT3A knockdown rescued SOD2 expression, suppressed mitochondrial oxidative burden, and ameliorated fibrosis. Clinically, idiopathic pulmonary fibrosis (IPF) patient tissues exhibited elevated DNMT3A levels, diminished SOD2 expression, and marked mitochondrial dysfunction, corroborating our experimental findings. These results unveil a novel DNMT3A/SOD2 axis as an epigenetic regulator of mitochondrial redox dysregulation-driven fibrosis, providing a potential therapeutic avenue for targeting oxidative damage in pulmonary fibrotic disorders.