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

TL;DR

This review explores how copper balance in the gut affects gut health, immunity, and diseases like cancer, and suggests new therapeutic strategies targeting copper.

Contribution

The paper systematically evaluates copper-targeted therapies and highlights unresolved challenges in copper homeostasis research.

Findings

Copper homeostasis modulates gut iron metabolism, barrier integrity, and immunity.

Copper dyshomeostasis contributes to diseases like Menkes, Wilson, and intestinal cancers.

Copper-targeting agents show therapeutic potential in oncology, but challenges remain.

Abstract

What are the main findings?
This review delineates the molecular machinery of intestinal copper absorption and transport, focusing on key transporters and regulatory mechanisms.We elucidate how copper homeostasis acts as a central modulator of gut iron metabolism, barrier integrity, mucosal immunity, the microbiome, and the gut–brain/liver axes.

This review delineates the molecular machinery of intestinal copper absorption and transport, focusing on key transporters and regulatory mechanisms.

We elucidate how copper homeostasis acts as a central modulator of gut iron metabolism, barrier integrity, mucosal immunity, the microbiome, and the gut–brain/liver axes.

What are the implications of the main findings?
The pathophysiological roles of copper dyshomeostasis in Menkes disease, Wilson disease, and intestinal cancers are comprehensively discussed.We explore the therapeutic potential and mechanisms of copper-targeting agents in oncology, evaluating current strategies and future directions.

The pathophysiological roles of copper dyshomeostasis in Menkes disease, Wilson disease, and intestinal cancers are comprehensively discussed.

We explore the therapeutic potential and mechanisms of copper-targeting agents in oncology, evaluating current strategies and future directions.

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.

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