LGMN regulates endothelial-to-mesenchymal transition via the p38 MAPK pathway to promote pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease driven by fibroblast activation and extracellular matrix deposition. Endothelial-to-mesenchymal transition (EndMT) critically contributes to vascular injury and fibrotic remodeling in IPF. Legumain (LGMN), a lysosomal cysteine protease involved in excessive extracellular matrix processing and signaling modulation, has been implicated in vascular remodeling and fibrosis. This study aimed to investigate whether LGMN influences pulmonary fibrosis by regulating the EndMT process. Independent transcriptomic analyses revealed LGMN is significantly upregulated in IPF and associated with poor prognosis. Publicly available single-cell RNA sequencing datasets identify endothelial cells as a major source of elevated LGMN in human IPF and murine fibrosis, with LGMN expression positively correlating with disease severity. Our studies demonstrated that LGMN knockdown in endothelial cells inhibited EndMT and enhanced migratory and tube formation capabilities; conversely, LGMN overexpression promoted EndMT and suppressed these functions. Transcriptomic profiling indicated that LGMN knockdown significantly influenced the p38 MAPK signaling pathway. To validate the mechanism, pharmacological inhibition of p38 MAPK reduced EndMT and partially reversed LGMN overexpression-induced EndMT. In conclusion, these results indicate LGMN promotes pulmonary fibrosis by activating the p38 MAPK pathway to regulate EndMT, suggesting its potential as a therapeutic target for pulmonary fibrosis.