Atg5 inhibits fibroblast activation and promotes alveolar regeneration to alleviate pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic disease, alveolar epithelial injury and fibroblast activation are two key stages in the progression of the disease. Under injury, autophagy often initiated to maintain cell survival and promote tissue regeneration. Here, we show that autophagy, a conserved cellular process, is upregulated in the mesenchymal cells of lung tissue in IPF patients and in a murine model of bleomycin-induced fibrosis. Our findings indicate that Atg5, a crucial autophagy-related gene, when conditionally deleted in mesenchymal cells, renders mice more susceptible to bleomycin-induced fibrosis. Mechanistically, this is mainly due to the loss of Atg5 exacerbating the activation of fibroblasts induced by TGF-β1, the proliferation of myofibroblasts, and the deposition of extracellular matrix. Intriguingly, as an important niche for alveolar type 2 (AT2) cells, the absence of Atg5 impairing the secretion of factors essential for AT2 cell proliferation and differentiation. These results indicated that autophagy can inhibit the differentiation of fibroblasts into myofibroblasts resulting in extracellular matrix deposition, while promoting alveolar epithelial regeneration. Screening for small molecule compounds that enhance the expression of Atg5 can effectively alleviate the progression of bleomycin-induced lung fibrosis in mice. In summary, our data support the possibility that Atg5 could be a potential clinical target for IPF management.