Background: Lung fibrosis is one of the most challenging sequelae of lung injury, without any treatment option available until now. It has been well known that autophagy has protective roles in pulmonary fibrosis. We aimed to evaluate the effects of Ezetimibe, an FDA-approved lipid-lowering agent and an autophagy activator, in preclinical models of pulmonary fibrosis.

Methods: Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro study. Non-cytotoxic dose of Ezetimibe was treated in TGF?1-induced myofibroblasts. RNA sequencing and Gene Set Enrichment Analysis were performed to prove the therapeutic mechanism of Ezetimibe. Oropharyngeal aspiration of Bleomycin induced pulmonary fibrosis in mice. Seven days after Bleomycin, a human equivalent dosage (2mg/kg) of Ezetimibe was orally gavaged to mice until sacrificed on day 21.

Results: Ezetimibe inhibited myofibroblast differentiation and activated autophagy at the transcriptomic level. Further mechanistic studies revealed that autophagic flux was increased by Ezetimibe treatment, and its inhibition led to the accumulation of COL1A1. Similarly, Ezetimibe protected mice from bleomycin-induced pulmonary fibrosis by inhibiting mTORC1 activity, followed by increased autophagic flux in mouse lung samples.

Conclusions: Ezetimibe may be repurposed for treating lung fibrosis. Further clinical validation is needed.