Extracellular Matrix Protein 1 (ECM1) levels predict the clinical outcome in human lung fibrosis

Fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), represent a major global health burden, characterized by enhanced extracellular matrix (ECM) deposition and remodelling, culminating in respiratory failure. Despite advances, predictors of IPF progression and mortality remain inadequate. Hypoxia-inducible factor (HIF) pathway activation has emerged as a critical player in IPF pathogenesis. We identified elevated HIF activity in alveolar macrophages and demonstrated that a HIF gene signature predicts mortality in IPF. Focusing on secreted HIF-regulated factors, we identified extracellular matrix protein 1 (ECM1) as a key mediator. ECM1 expression was elevated in hypoxic macrophages, IPF lungs, and a bleomycin-induced lung fibrosis model, correlating with poor survival. Mechanistically, ECM1 interacts with TGFbeta-induced integrin beta3 to activate the HIF pathway in lung fibroblasts, enhancing the expression of collagen-modifying enzymes PLOD2 and LOXL2, promoting pathological ECM remodelling. This ECM1-TGFbeta-integrin beta3 axis disrupts normal tissue repair, perpetuating fibrosis. These findings elucidate ECM1's pivotal role in IPF pathogenesis and highlight its potential as a prognostic biomarker and therapeutic target.