Attenuation of Cuproptosis Through Histone Deacetylase Inhibition: A Novel Strategy for Alleviating Acute Lung Injury

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Abstract Background: Acute respiratory distress syndrome/ acute lung injury (ARDS/ALI) are significant causes of respiratory failure, associated with high mortality and often underrecognized. The pathophysiology of ALI is complex, with growing evidence indicating the involvement of regulated cell death (RCD) mechanisms in their progression. Among these, cuproptosis, a recently identified copper-dependent form of RCD linked to mitochondrial dysfunction, may play a crucial role due to copper's established impact on lung injury. Histone deacetylases (HDACs) have also been observed to interact with copper, and HDAC inhibition has been reported to restore mitochondrial dysfunction, suggesting that HDAC inhibitors may modulate cuproptosis. This study aims to investigate the potential of targeting cuproptosis to alleviate ARDS/ALI. Methods: First, we examined the role of cuproptosis in a lipopolysaccharide (LPS)-induced ALI mouse model. Then, we assessed the changes in lung injury severity and the extent of cuproptosis after treatment with an HDAC inhibitor in mouse and epithelial cells (A549 cells) with ALI model. We evaluated these aspects using bulk RNA sequencing, histological staining, and molecular biology techniques. Results: The expression of cuproptosis-related genes was significantly altered in lung tissue of mice following intratracheal LPS administration. We observed the loss of Fe-S cluster proteins and the aggregation of lipoylated proteins in the lung tissue of LPS-treated mice, indicating that cuproptosis had occurred. Furthermore, treatment with sodium butyrate (SB), an HDAC inhibitor, alleviated the loss of Fe-S cluster proteins and reduced the aggregation of lipoylated proteins. Additionally, SB mitigated epithelial injury and acute lung injury in these mice, and restored the changes in copper transport proteins and Fe-S cluster proteins in A549 cells treated with LPS. Conclusion: Cuproptosis is a key pathway in the progression of ALI. SB can alleviate ALI by inhibiting cuproptosis. Keywords: Acute respiratory distress syndrome, acute lung injury, cuproptosis, copper-induced cell death.

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