Abstract Idiopathic Pulmonary Fibrosis (IPF) is a chronic, irreversible, aging-associated, and ultimately fatal lung disease. The median survival of pulmonary fibrosis patients is only 4-5 years. There is no treatment to reverse fibrosis and cure IPF. Development of anti-fibrotic therapeutics is an unmet need in the treatment of IPF. The relentless progression of IPF is due in part to the failure of fibrosis resolution. The development of therapies for IPF relies on the comprehensive understanding of fibrosis resolution pathways. Accumulating evidence shows that activation of BMPs signaling induces myofibroblast de-differentiation and fibrosis resolution. A key receptor, BMP receptor II (BMPRII), in BMPs signaling has been shown to be reduced in fibrotic lungs; thus, restoration of BMPRII in fibrotic lungs is a potential therapy to treat IPF. However, molecular regulation of BMPRII stability has not been well studied. In our preliminary data, we discovered that (i) BMPRII is degraded in the lysosome system in response to TGF-β1 and lipid peroxidation inducers, which play critical roles in the development of lung fibrosis; (ii) Nedd4L stabilizes BMPRII; (iii) downregulation of Nedd4L reduced BMP4 signaling and the effects were rescued by overexpression of BMPRII; (iv) overexpression of Nedd4L promoted de-differentiation of lung myofibroblasts. Based on these novel observations, we hypothesized that Nedd4L promotes BMPRII stability and facilitates BMPs/BMPRII-mediated myofibroblast de-differentiation and pulmonary fibrosis resolution. We propose three Specific Aims to evaluate our hypothesis. First, we will determine the regulatory mechanisms by which Nedd4L stabilizes BMPRII. We will identify the ubiquitination and Nedd4L docking sites on BMPRII and determine the effect of Nedd4L-mediated K63-linked ubiquitination on BMPRII internalization and stability. Next, we will determine if Nedd4L suppression is essential for TGF-β1- and lipid peroxidation-induced BMPRII degradation. Finally, we will determine if Nedd4L facilitates lung fibrosis resolution through stabilization of BMPRII and promotion of BMPs-mediated myofibroblast de-differentiation and inactivation. We will determine if elevated BMPRII stability by Nedd4L facilitates myofibroblast de-differentiation in ex-vivo cultured lung myofibroblasts. An inducible fibroblast specific Nedd4L depletion mouse will be used in both resolving and non- resolving lung fibrosis models. The proposed studies will address key knowledge gaps regarding molecular regulation of BMPRII stability and anti-fibrotic effects of BMPs/BMPRII. Success of the proposed studies will suggest that targeting Nedd4L/BMPRII to rescue BMPRII expression in fibrotic lungs may lead to new opportunities to halt pro-fibrotic progression and promote fibrosis resolution.