Multifaceted Role of Copper Homeostasis in Gut Health: From Molecular Mechanisms to Therapeutic Interventions

Intestinal copper homeostasis governs gut health through its dual roles as an enzymatic cofactor and signaling mediator. This review discusses the molecular basis of copper absorption/transport, genetic regulation, and its functional impacts. Copper-dependent enzymes maintain intestinal barrier function and metabolism, while copper availability shapes the composition of gut microbiota and mucosal immunity. The dysregulation of copper homeostasis, specifically pathological accumulation, contributes to the development of CRC by inducing dysbiosis of gut microbiota, chronic inflammation, and metastasis. This review systematically evaluates copper-targeted therapies and the associated unresolved challenges. Future efforts should prioritize defining cell-specific copper handling, metal interaction networks, and the copper-gut microbiota-immune axis in non-cancer pathologies. Moreover, future studies should also focus on developing stratified biomarker panels and spatially precise interventions to harness copper biology for diagnostic and therapeutic innovation.