Dysregulated Copper Metabolism-Induced Cuproptosis Contributes to Mitochondrial Dysfunction and Macrophage Inflammatory Response in Acute Lung Injury

Aims: To determine whether dysregulated copper metabolism and cuproptosis contribute to acute lung injury (ALI), and to evaluate whether targeting copper homeostasis mitigates lung inflammation and injury. Results: Integrative analysis of RNA-seq data from patients with severe community-acquired pneumonia revealed increased enrichment of copper metabolism-related gene sets and differential expression of cuproptosis-related genes. Notably, immune deconvolution of patient RNA-seq data demonstrated prominent macrophage enrichment, suggesting that macrophages represent a major cell group in which dysregulated copper metabolism may occur during ALI. In a lipopolysaccharide (LPS)-induced mouse ALI model, lung copper levels were elevated, accompanied by molecular features of cuproptosis, including increased DLAT oligomerization and destabilization of Fe–S cluster proteins. Pretreatment with the copper chelator tetrathiomolybdate alleviated lung injury and inflammatory response, while suppressing cuproptosis-related molecular features in vivo . In alveolar macrophages, LPS challenge increased intracellular Cu + concentration and promoted DLAT oligomerization, and impaired Fe–S protein stability. Mechanistically, both copper chelation and knockdown of upstream cuproptosis regulator reduced DLAT oligomerization, restored Fe–S proteins, alleviated mitochondrial dysfunction, and decreased CD86 + macrophage polarization. Importantly, altered expression of copper transporters was observed, suggesting a remodeling of copper metabolic homeostasis during ALI. Innovation and Conclusion: This study identifies cuproptosis as a previously unrecognized driver of ALI, mechanistically linking copper dysregulation to mitochondrial damage and inflammatory activation of alveolar macrophages, and demonstrates the therapeutic benefit of copper chelation or cuproptosis suppression. Antioxid. Redox Signal. 44, 770–791.