Oxidative stress and copper imbalance in hypoxic-ischemic encephalopathy: Exploring new targets for neuroprotective...

Hypoxic-ischemic encephalopathy (HIE) remains a leading cause of neonatal mortality and neurodevelopmental disorders. Hypothermic therapy is the only moderately effective treatment available, but its benefits are limited. This article examines the interplay between oxidative stress and copper homeostasis imbalance in HIE pathogenesis, focusing on how oxidative stress disrupts copper homeostasis, promotes copper accumulation, and triggers multiple cell death pathways, including cuproptosis, ferroptosis, and apoptosis. Oxidative stress perturbs brain copper ion balance through several mechanisms, such as blood-brain barrier damage and impaired function of copper transporters (such as copper transporter 1 and copper-transporting P-type ATPase 1), leading to neuronal copper accumulation. Excess intracellular copper ions then promote tricarboxylic acid cycle enzyme acetylation, protein aggregation, and degradation of iron-sulfur cluster cofactors, ultimately inducing cuproptosis. Copper dysregulation also contributes to ferroptosis, apoptosis, and other cell death pathways, forming a complex pathological network that exacerbates neuronal damage. In conclusion, this article proposes an "oxidative stress-copper homeostasis imbalance-cell death" pathological loop and discusses associated targeted therapeutic strategies, including copper-homeostasis modulation and mitochondrial cofactor-based interventions, providing new insights for HIE treatment.