Journal of inflammation research · 2025
The Role of Cuproptosis in Hyperoxia-Induced Lung Injury and Its Potential for Treatment.
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Yu Kaihua, Gu Yunfei, Yao Ying, Li Jianchun, Chen Suheng, Guo Hong, Li Yulan, Liu Jian
Аннотация
BACKGROUND: Oxygen supplementation is essential for patients with a multitude of diseases but can cause severe hyperoxia-induced lung injury (HLI), necessitating the identification of therapeutic targets to improve clinical outcomes. Cuproptosis, a novel copper-dependent form of cell death characterized by proteotoxic stress resulting from lipoylated protein aggregation and loss of iron-sulfur cluster proteins, is distinct from other forms of cell death. However, the role of cuproptosis in HLI remains unclear.
METHODS: We established an HLI model in MLE-12 cells and C57BL/6 mice to investigate the involvement of cuproptosis in hyperoxia-induced toxicity.
RESULTS: We observed a time-dependent increase in the cuproptosis-related gene Fdx1 under hyperoxia. Moreover, hyperoxia activated the membrane-associated copper transporter SLC31A1 and significantly elevated copper levels in MLE-12 cells, as well as in the serum and lung tissue of C57BL/6 mice. Further analysis revealed that hyperoxia significantly altered the expression of cuproptosis-related genes without affecting DLAT levels, but significantly increased lipoylated-DLAT levels. ELISA, CCK-8 assays, HE staining, lung wet-to-dry weight ratio, and bronchoalveolar lavage fluid analysis demonstrated that treatment with the cuproptosis inhibitor TTM reduced pro-inflammatory cytokines (TNF-α and IL-1β) and alleviated hyperoxia-induced injury in both MLE-12 cells and C57BL/6 mice.
CONCLUSION: Our study identifies the involvement of cuproptosis in HLI, providing new insights into the pathogenesis of hyperoxic lung injury and potential therapeutic strategies.
METHODS: We established an HLI model in MLE-12 cells and C57BL/6 mice to investigate the involvement of cuproptosis in hyperoxia-induced toxicity.
RESULTS: We observed a time-dependent increase in the cuproptosis-related gene Fdx1 under hyperoxia. Moreover, hyperoxia activated the membrane-associated copper transporter SLC31A1 and significantly elevated copper levels in MLE-12 cells, as well as in the serum and lung tissue of C57BL/6 mice. Further analysis revealed that hyperoxia significantly altered the expression of cuproptosis-related genes without affecting DLAT levels, but significantly increased lipoylated-DLAT levels. ELISA, CCK-8 assays, HE staining, lung wet-to-dry weight ratio, and bronchoalveolar lavage fluid analysis demonstrated that treatment with the cuproptosis inhibitor TTM reduced pro-inflammatory cytokines (TNF-α and IL-1β) and alleviated hyperoxia-induced injury in both MLE-12 cells and C57BL/6 mice.
CONCLUSION: Our study identifies the involvement of cuproptosis in HLI, providing new insights into the pathogenesis of hyperoxic lung injury and potential therapeutic strategies.