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Sepsis-induced cardiomyopathy (SCM) is driven by copper homeostasis imbalance, where both excess and deficiency disrupt cellular function and induce cardiomyocyte injury. This review synthesizes pathophysiological mechanisms involving abnormal copper metabolism, lipid disorders, endoplasmic reticulum stress, and various regulated cell death forms like cuproptosis. It further evaluates therapeutic strategies ranging from chelators to nanopreparations while identifying current research gaps.

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Abstract

Sepsis-induced cardiomyopathy (SCM) is a severe, mortality-increasing sepsis complication, with copper homeostasis imbalance as a key pathogenic factor. Copper (Cu) plays a dual role: as an essential enzyme cofactor, it regulates vital processes including energy metabolism and redox balance; however, both excess and deficiency disrupt cellular homeostasis and induce cardiomyocyte injury. This review summarizes core pathophysiological mechanisms linking copper homeostasis imbalance to SCM, including abnormal copper metabolism (dysregulated uptake/transport/excretion), lipid metabolism disorders, endoplasmic reticulum stress (ERS), and various regulated cell death (RCD) forms (cuproptosis, apoptosis, autophagy, pyroptosis, ferroptosis, necrosis). We also elaborate potential therapeutic strategies targeting copper homeostasis, including copper chelators, copper transport inhibitors, copper-mediated RCD modulators, multi-target natural products, nanopreparations, and latest advances in copper-based myocardial injury therapy. Finally, we address current research limitations and outline future directions, such as exploring copper-related cell death markers, clarifying underexplored copper signaling in SCM, and developing innovative precision therapies. This review offers a comprehensive theoretical foundation for further investigating copper homeostasis in SCM and developing novel therapies.

Key findings

  • Copper homeostasis imbalance serves as a key pathogenic factor in sepsis-induced cardiomyopathy, affecting energy metabolism and redox balance.
  • Pathogenesis involves dysregulated copper uptake/transport/excretion leading to lipid metabolism disorders and endoplasmic reticulum stress.
  • Therapeutic interventions targeting copper homeostasis include chelators, transport inhibitors, modulators of regulated cell death, and multi-target natural products.

Keywords

HomeostasisCardiomyopathyCell metabolismCell biologyCopper deficiencyProgrammed cell death

Identifiers

DOI
10.3389/fcell.2026.1753386
Journal
Frontiers in Cell and Developmental Biology
Year
2026