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The zinc–nitric oxide axis in acute brain injury: Convergent oxidative–nitrative stress, peroxynitrite signaling, and therapeutic targets

Year: 2026

Type: article

Abstract: Acute brain injuries are characterized by secondary cascades driven by oxidative and nitrative stress. While the roles of excitotoxicity and neuroinflammation in acute brain injury are well recognized, emerging evidence indicates that the interaction between dysregulated zinc (Zn 2+ ) signaling and nitric oxide (NO) biology forms a central metal–redox system that amplifies neuronal injury. Here, we propose the zinc–nitric oxide (Zn–NO) axis as a unified mechanistic framework linking synaptic dysfunction, mitochondrial failure, and neuroinflammatory escalation. Pathological Zn 2+ accumulation, arising from vesicular release, intracellular mobilization, and disrupted transporter homeostasis, impairs mitochondrial respiration, enhances reactive oxygen species (ROS) generation, and disrupts redox buffering capacity. In parallel, NO derived from neuronal, endothelial, and inducible nitric oxide synthases reacts with superoxide to form peroxynitrite (ONOO − ), a potent mediator of oxidative and nitrative damage. Zn 2+ and NO converge primarily within mitochondria, where their interaction promotes superoxide production, ONOO − formation, and bioenergetic collapse. This coupling further disrupts glutathione homeostasis, activates NADPH oxidase, destabilizes lysosomal function, and amplifies inflammatory signaling pathways governing microglial activation and blood–brain barrier integrity. These processes drive neuronal death through apoptosis, ferroptosis-associated lipid peroxidation, and inflammation-linked degeneration. In this review, we integrate experimental and translational evidence supporting the finding that the Zn–NO–ONOO - axis is a central driver of redox-dependent injury, and highlight therapeutic strategies targeting this network, including zinc modulation, NO pathway regulation, peroxynitrite scavenging, and mitochondrial protection. In conclusion, targeting the Zn–NO axis as a unified redox hub may limit secondary injury propagation and improve neuroprotection in acute brain injury.

Source: Redox Biology

DOI: 10.1016/j.redox.2026.104173

Authors: Hyun Wook Yang, Min Kyu Park, Hyun Ho Jeong, Sang Won Suh

Institution: Hallym University

Language: English

Topic: Traumatic Brain Injury and Neurovascular Disturbances

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,310