Cuproptosis in Sepsis: Cell Type-Specific Mechanisms and Clinical Prospects

Sepsis is a life-threatening clinical syndrome caused by a severely dysregulated host response to infection. As a major global health challenge, it continues to exhibit high mortality. Copper, an essential trace element crucial for biological homeostasis, is central to a recently defined form of cell death: cuprotosis. This novel, copper-dependent mitochondrial cell death pathway is mechanistically distinct from classical apoptosis and pyroptosis. In sepsis, cuprotosis contributes significantly to immune dysfunction and organ failure by mediating the death of both immune cells (e.g. macrophages, lymphocytes) and parenchymal cells (e.g. cardiomyocytes, renal tubular cells). Therefore, modulating this regulatory mechanism in a cell type-specific manner may represent a novel potential therapeutic avenue for sepsis, although substantial clinical validation is still required. This review systematically outlines the core mechanisms of cuprotosis, elucidates its pathophysiological role in sepsis, and evaluates the potential and challenges of targeting cuprotosis for sepsis therapy.