Copper homeostasis and cuproptosis represent emerging targets for therapeutic intervention in inflammatory diseases
Wenming Yang, Chuqiao Xiao, Jie Zheng, Jie Song, Xiangguang Li
Abstract
Copper homeostasis dysregulation and the ensuing process of cuproptosis have gained considerable attention as potential therapeutic avenues in the management of inflammatory diseases. As a vital trace element, copper is integral to inflammatory responses, influencing oxidative stress, mitochondrial metabolism, and immune epigenetics. Cuproptosis is characterized as a distinctive copper-dependent cell death mechanism, distinguished by the aberrant aggregation of mitochondrial lipoylated proteins, destabilization of iron-sulfur cluster proteins, and morphological changes such as mitochondrial shrinkage and plasma membrane rupture. This distinguishes it from conventional regulated cell death pathways. Key regulatory genes play crucial roles in modulating copper uptake, efflux, and the enzymatic processes associated with the tricarboxylic acid cycle, exhibiting significant dysregulation in inflammatory states. Copper chelators effectively attenuate inflammation by lowering bioavailable copper levels and curbing reactive oxygen species production. Simultaneously, copper ionophores such as disulfiram promote targeted intracellular copper redistribution, although their tissue specificity and safety profiles require further optimization. Novel strategies, including the nuanced modulation of copper chaperones, the development of functionalized nanoscale copper delivery systems, and innovative copper-based photothermal therapies, provide promising avenues for inflammation regulation. Future investigations should focus on elucidating the molecular dynamics between cuproptosis and immune microenvironment, advancing high-throughput and artificial intelligence-driven drug screening methodologies, and enhancing the clinical applicability of tissue-specific copper metabolic imaging alongside targeted delivery systems. These efforts may ultimately facilitate precision therapeutic interventions in the context of inflammatory diseases.