Carbon monoxide neurotoxicity and delayed encephalopathy: ferroptosis–Nrf2 mechanisms and therapeutic implications

Abstract

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a common and highly disabling neurological complication of carbon monoxide (CO) poisoning, and it markedly affects long-term cognitive function and overall prognosis. Recent advances have improved our understanding of its pathogenesis, yet effective mechanism-based treatments remain lacking. Among these advances, ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is now recognized as a key contributor to CO-related neurological injury. In parallel, nuclear factor erythroid 2-related factor 2 (Nrf2), a central regulator of cellular antioxidant defense and iron homeostasis, plays a crucial protective role by suppressing ferroptosis and limiting neuronal damage. In this review, we focus on the ferroptosis–Nrf2 axis and summarize recent basic and preclinical evidence. We examine how this axis may link acute CO toxicity to delayed neuropathological changes and distinguish CO-specific evidence from supportive findings in non-CO central nervous system injury models. We also identify key priorities for future research and discuss the therapeutic implications of targeting this axis.