Copper in Human Health and Disease: Insights from Inherited Disorders

In recent years, our understanding of copper metabolism in humans has advanced considerably, driven in large part by insights from genetic disorders. Studies of Menkes disease, Wilson disease, MEDNIK (mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia) and KIDAR (autosomal recessive keratitis, ichthyosis, deafness) syndromes, and most recently CTR1 deficiency, have illuminated the fundamental principles of copper acquisition, intracellular distribution, and systemic elimination. These discoveries not only revealed the canonical roles of CTR1, ATP7A, and ATP7B but also uncovered auxiliary pathways of copper uptake, novel chaperone and organelle-specific distribution mechanisms, and the importance of trafficking adaptors in maintaining copper balance. Beyond its classical enzymatic functions, copper has emerged as a dynamic regulator of cell signaling, autophagy, metabolism, and immune surveillance, with mitochondrial dysfunction and cuproptosis representing key pathogenic outcomes of copper imbalance. The expanding view of copper as both a nutrient and a signaling ion highlights the complexity of its physiological regulation. In this review, we summarize the current knowledge of human copper homeostasis, focusing on how lessons from inherited disorders continue to redefine our understanding of copper physiology and inform therapeutic approaches.