Work

Mitophagy promotes lung repair and regeneration by restoring epithelial metabolic fitness

Year: 2026

Type: article

Abstract: 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.

Source: Nature Communications

DOI: 10.1038/s41467-026-71728-x