Lipolysis Engages CD36 to Promote ZBP1-Mediated Necrosis Impairing Lung Regeneration in COPD

Lung parenchyma destruction represents a severe condition commonly found in chronic obstructive pulmonary disease (COPD), the leading cause of morbidity and mortality worldwide. Promoting lung regeneration is crucial for achieving clinical improvement. However, no therapeutic drugs are approved to improve the regeneration capacity due to incomplete understanding of the underlying pathogenic mechanisms. Here, we identify a positive feedback loop formed between adipose triglyceride lipase (ATGL)-mediated lipolysis and overexpression of CD36 specific to lung epithelial cells, contributing to disease progression. Genetic deletion of CD36 in lung epithelial cells and pharmacological inhibition of either ATGL or CD36 effectively reduce COPD pathogenesis and promote lung regeneration in mice. Mechanistically, disruption of the ATGL-CD36 loop rescued Z-DNA binding protein 1 (ZBP1)-induced cell necroptosis and restored WNT/β-catenin signaling. Thus, we uncover a previously unrecognized crosstalk between lipolysis and lung epithelial cells, suggesting the regenerative potential for therapeutic intervention by targeting the ATGL-CD36-ZBP1 axis in COPD.