Lipolysis engages CD36 to promote ZBP1-mediated necroptosis-impairing lung regeneration in COPD

Lung parenchyma destruction represents a severe condition commonly found in chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Promoting lung regeneration is crucial for achieving clinical improvement. However, no therapeutic drugs are approved to imp...

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Veröffentlicht in:Cell reports. Medicine 2024-09, Vol.5 (9), p.101732, Article 101732
Hauptverfasser: Wang, Jiazhen, Wang, Ru, Li, Yicun, Huang, Jiahui, Liu, Yang, Wang, Jiayi, Xian, Peng, Zhang, Yuanhang, Yang, Yanmei, Zhang, Haojian, Li, Jiansheng
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Sprache:eng
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Zusammenfassung:Lung parenchyma destruction represents a severe condition commonly found in chronic obstructive pulmonary disease (COPD), a 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 rescues Z-DNA binding protein 1 (ZBP1)-induced cell necroptosis and restores WNT/β-catenin signaling. Thus, we uncover a crosstalk between lipolysis and lung epithelial cells, suggesting the regenerative potential for therapeutic intervention by targeting the ATGL-CD36-ZBP1 axis in COPD. [Display omitted] •Lipolysis is increased in COPD, and ATGL inhibition alleviates COPD•CD36 is selectively upregulated in lung epithelial cells and promotes COPD•Lipolysis-CD36 positive feedback loop impairs lung regeneration via ZBP1•The ATGL-CD36-ZBP1 axis can be therapeutically exploited Wang et al. identify a positive feedback loop formed between ATGL-mediated lipolysis and the overexpression of CD36 in lung epithelial cells that dampens lung regeneration through ZBP1-induced necroptosis in chronic obstructive pulmonary disease (COPD) and suggest that the ATGL-CD36-ZBP1 axis can be therapeutically exploited.
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2024.101732