Mitophagy promotes lung repair and regeneration by restoring epithelial metabolic fitness

Alveolar Type II cells (AT2s) are the stem cells responsible for both lung homeostasis and regeneration. Mitochondrial dysfunction in AT2 cells has been implicated in both chronic and acute injury-induced alveolar diseases, including idiopathic pulmonary fibrosis (IPF) and viral pneumonia. However, the role of mitochondrial homeostasis in post-injury lung repair and regeneration remains elusive. Here we demonstrate that genetic depletion of Ubiquitin Specific Peptidase 30 (USP30), a negative regulator of mitophagy, boosts mitophagy and restores mitochondrial function in AT2 cells, leading to protection from injury-induced apoptosis and enhanced stem cell activity. Both global and AT2-specific Usp30 knockout (KO) promote alveolar regeneration, protecting the mice from bleomycin-induced lung fibrosis and influenza pneumonia. Moreover, pharmacological inhibition of USP30 effectively alleviates these conditions. Together, our findings reveal a previously underappreciated role for mitophagy in lung injury and repair and highlight USP30 inhibition as a promising therapeutic strategy for treating alveolar diseases. USP30, a negative regulator of mitophagy, is identified as a potential therapeutic target for lung fibrosis and viral pneumonia. Inhibition of USP30 protects alveolar epithelial cells from apoptosis and enhances alveolar regeneration.