Abstract

Oxidative stress is a central, converging mechanism underlying neurotoxicity in a broad range of systemic disorders, 
including diabetes mellitus, malaria, and hepatic dysfunction. In these conditions, excessive reactive oxygen and 
nitrogen species (ROS/RNS), impaired antioxidant defenses, mitochondrial dysfunction, and neuroinflammation 
interact to damage neurons and glia, disrupt the blood–brain barrier (BBB), and impair synaptic and cognitive 
function. Understanding shared molecular pathways allows cross-fertilization of therapeutic strategies. This review 
synthesizes current knowledge on oxidative-stress–driven neural injury across diabetes, cerebral malaria, and liver 
disease, and evaluates emerging neuroprotective strategies: direct and indirect antioxidants, Nrf2 pathway 
modulators, mitochondrial-targeted therapies, anti-inflammatory and immunomodulatory agents, BBB-stabilizing 
approaches, nanodelivery systems, metabolic and lifestyle interventions, and regenerative/repair modalities. 
Preclinical advances-such as mitochondria-targeted peptides, Nrf2 activators, and nanoparticle-facilitated delivery 
of antioxidants-show promise, and some repurposed drugs (metformin, statins) demonstrate pleiotropic effects 
across disorders. However, translation is challenged by disease heterogeneity, timing of therapy relative to injury, 
limited CNS penetration, and inadequate biomarkers. We highlight priority areas for translational research: 
combination regimens that target oxidative stress and inflammation simultaneously, precision delivery systems to 
cross or protect the BBB, robust biomarkers for oxidative injury and therapeutic response, and early-intervention 
trials in stratified patient populations. Integrating mechanistic insights from diabetes, malaria, and hepatic 
dysfunction can accelerate development of broadly applicable neuroprotective strategies that mitigate oxidative
stress–mediated neural injury in systemic disease.