WSB1, a Hypoxia-Inducible E3 Ligase, Promotes Myofibroblast Accumulation and Attenuates Alveolar Epithelial Regeneration in Mouse Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease for which there is no curative therapy available. Repetitive alveolar epithelial injury repair, myofibroblast (MYF) accumulation and excessive collagen deposition are key pathological features of IPF, eventually leading to cellular hypoxia and respiratory failure. The precise mechanism driving this complex maladaptive process remains inadequately understood. WSB1 (WD repeat and SOCS box containing 1) is an E3 ubiquitin ligase, the expression of which is strongly associated with hypoxia, and forms a positive feedback loop with HIF-1α under anoxic condition. In this study, we explored the expression, cellular distribution and function of WSB1 in bleomycin (BLM)-induced mouse lung injury and fibrosis. WSB1 expression was highly induced by BLM injury and correlated with the progression of lung fibrosis. Significantly, conditional deletion of Wsb1 in adult mice ameliorated BLM-induced pulmonary fibrosis. Phenotypically, Wsb1-deficient mice exhibited reduced lipofibroblast (LIF) to MYF transition, but enhanced alveolar type 2 (AT2) proliferation and differentiation into AT1 following BLM injury. Proteomic analysis of mouse lung tissues identified Caveolin 2 as a potential downstream target of WSB1, contributing to BLM-induced epithelial injury repair and fibrosis. Our findings unravel a vital role for WSB1 induction in lung injury repair, thus highlighting it as a potential therapeutic target for pulmonary fibrosis.