MG53-mediated membrane repair attenuates pulmonary fibrosis by antagonizing TGF-β1-driven epithelial mesenchymal...

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive disease with limited options for therapy. Mitsugumin 53 (MG53), a key factor involved in cell membrane repair, emerges as a protector in diverse disease models and cell injury. Although its role in pulmonary fibrosis is not well understood, this study focuses on exploring the function of MG53 in IPF and evaluating the therapeutic potential of recombinant MG53 protein.

Circulating MG53 levels were quantified in IPF patients and healthy controls. A pulmonary fibrosis model was induced in C57BL/6J mice using bleomycin (BLM), and the mice were then treated with either recombinant human MG53(rhMG53) or saline. In vitro, MLE-12 cells were subjected to TGF-β1 stimulation with or without rhMG53 to explore the affected mechanisms, with a focus on the TGF-β1/Smad signaling pathway and epithelial-mesenchymal transition (EMT).

Circulating MG53 levels were significantly decreased in IPF patients and positively correlated with lung function parameters. Similarly, MG53 expression was decreased in the BLM-exposed mice lungs. Treatment with rhMG53 improved survival, attenuated weight loss, and enhanced pulmonary function in BLM-injured mice. Mechanistically, rhMG53 decreased TGF-β1 levels in bronchoalveolar lavage fluid and inhibited Smad2/3 phosphorylation both in vivo and in TGF-β1-stimulated MLE-12 cells. rhMG53 administration did not cause any signs of systemic toxicity.

MG53 deficiency is associated with IPF severity, and supplementation with rhMG53 mitigates BLM-induced pulmonary fibrosis by preventing TGF-β1/Smad signaling and EMT. These findings highlight MG53 as a potential protein-based therapy and biomarker of pulmonary fibrosis.