Trace Element Dysregulation and Oxidative Stress in Experimental and Clinical Disorders: Mitochondrial Redox Mechanisms, Ferroptosis, and Translational Therapeutic Perspectives.

Trace elements are integral regulators of mitochondrial bioenergetics, antioxidant defense, immune signaling, and regulated cell death. However, disruption of trace element homeostasis may convert physiologically essential micronutrients into active contributors to oxidative injury, mitochondrial dysfunction, inflammation, ferroptosis, and toxicity. This PRISMA-ScR-informed critical review maps and critically evaluates experimental, observational, and interventional evidence linking selenium, zinc, iron, copper, and manganese dysregulation with mitochondrial redox dysfunction and disease progression. Particular emphasis is placed on quantitative evidence, methodological strength, hierarchical appraisal of study designs, and explicit distinction between associative, mechanistically supported, and interventional evidence. Mechanistic evidence is synthesized across glutathione peroxidase 4-dependent ferroptosis, iron-driven lipid peroxidation, cuproptosis, mitochondrial quality control, AMPK/SIRT1/PGC-1α signaling, cGAS-STING activation, macrophage polarization, and interconnected regulated cell-death networks. Current evidence supports a bidirectional and context-dependent trace element-mitochondrial redox-ferroptosis axis rather than a simple relationship between isolated micronutrient deficiency and oxidative stress. Experimental studies provide comparatively strong mechanistic evidence, whereas much of the human literature remains observational and is limited by reverse causality, residual confounding, inconsistent biomarker assessment, and insufficient characterization of dose-response relationships. Both trace element deficiency and excess may be harmful, emphasizing the importance of quantitatively defining dose-response relationships, bioavailability, toxicity thresholds, and disease-specific therapeutic windows rather than pursuing indiscriminate supplementation. Future translation requires standardized analytical approaches, longitudinal and mechanistically informed interventional studies, quantitative characterization of exposure and toxicity, multi-element profiling, validated biomarkers of metal-dependent regulated cell death, and integration of multi-omics and artificial intelligence-assisted biomarker analysis. Precision modulation of trace element-redox networks may ultimately provide greater therapeutic potential than non-selective antioxidant strategies.