Nedd4L-mediated stabilization of morphogenetic protein receptor 2 in lung fibroblasts confers protection against pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease that advances over time and is ultimately life-threatening. Despite advances in antifibrotic therapies, disease progression remains largely unavoidable, highlighting the necessity for advancing mechanistic research and identifying new therapeutic options. Bone morphogenetic protein receptor 2 (BMPR2) is a key receptor for BMP signaling and exerts potent antifibrotic role in lung fibrosis; however, the molecular mechanisms regulating BMPR2 protein stability in fibrotic lungs remain poorly understood. In this study, we identify that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated protein 4-like (Nedd4L) as a critical regulator of BMPR2 stability in lung fibroblasts. BMPR2 levels are markedly reduced in lung fibroblasts derived from patients with IPF and in lung tissues from experimental lung fibrosis models. Mechanically, elevated lipid peroxidation in fibrotic lungs induces K48-linked ubiquitination of BMPR2, leading to its degradation and attenuation of BMPs-induced Smad1/5 phosphorylation. Notably, Nedd4L overexpression counteracts lipid peroxidation-induced BMPR2 degradation and promotes BMPs/BMPR2 signaling by shifting BMPR2 ubiquitination toward a stabilizing K63-linked polyubiquitination in lung fibroblasts. We further show that Nedd4L is regulated through threonine phosphorylated by Raf1 kinase in response to increased lipid peroxidation. In vivo, fibroblast-Nedd4L-deficient mice exacerbates experimental lung fibrosis, which is significantly alleviated by BMPR2 overexpression. Collectively, our findings reveal a previously unrecoganized regulatory mechanism of BMPR2 degradation in fibrotic lungs and indicate that stabilizing BMPR2 in lung fibroblasts may represent a promising approach for the treatment of lung fibrosis.