Inhibiting mitoNEET restores mitochondrial redox homeostasis and attenuates myofibroblast differentiation

Idiopathic pulmonary fibrosis is a chronic and incurable lung disease characterized by progressive destruction and scarring of lung tissue. A hallmark of Idiopathic pulmonary fibrosis is the accumulation of extracellular matrix produced by differentiated myofibroblasts. Recent studies have highlighted the role of reactive oxygen species and mitochondrial dysfunction in myofibroblast differentiation and disease progression. MitoNEET, also known as CDGSH iron-sulfur (Fe-S) domain-containing protein 1 (CISD1), is an outer mitochondrial membrane protein that contains iron-sulfur clusters and regulates mitochondrial function by controlling iron homeostasis and reactive oxygen species generation. However, the role of mitoNEET in redox signaling during fibrosis remains unclear. In this study, we investigated the role of mitoNEET in TGF-β-induced myofibroblast differentiation. We found that TGF-β treatment increased mitoNEET mRNA and protein levels in lung fibroblasts. Notably, pharmacological inhibition or short hairpin RNA-mediated knockdown of mitoNEET effectively attenuated TGF-β-induced myofibroblast differentiation, which was accompanied by a reduction in mitochondrial reactive oxygen species levels. Our findings indicate that mitoNEET regulates myofibroblast differentiation through redox-mediated mechanisms, highlighting its role as a redox regulator in fibrosis progression. Targeting mitoNEET to restore redox balance may provide a novel therapeutic strategy for idiopathic pulmonary fibrosis.