Nephronectin (NPNT) is a Crucial Determinant of Idiopathic Pulmonary Fibrosis: Modulating Cellular Senescence via the ITGA3/YAP1 Signaling Axis

Abstract Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease. While advancing age is recognized as the most significant risk factor for both the development and mortality associated with pulmonary fibrosis, precise mechanisms underlying this association remain elusive. Here, Nephronectin (NPNT) is identified as an antiaging molecule, a potential major regulator of the progression of pulmonary fibrosis. In IPF patients, a marked reduction in NPNT expression is detected in lung tissues, which correlated with a decline in lung function. The study reveals that NPNT deficiency exacerbates bleomycin‐induced senescence in alveolar epithelial cells, potentially intensifying fibrosis severity due to diminishes extracellular matrix turnover. Conversely, NPNT overexpression in the alveolar epithelium improves lung respiratory function and enhances resistance to aging and fibrosis. Mechanistically, NPNT inhibits the hyperactivation of LATS1 and MOB1, facilitates YAP1 nuclear translocation, and suppresses YAP1 ubiquitination and degradation, contingent upon the interaction between NPNT and ITGA3. Notably, pharmacological elevation of NPNT protein levels using Escin has been shown to alleviate pulmonary fibrosis and improve lung function in mice. The findings shed light on the key mechanism underlying stress‐induced senescence and fibrosis, and offer a promising framework for interventions targeting aging‐related diseases.