MicroRNAs at the crossroads of exercise and ferroptosis: a regulatory bridge

Ferroptosis is a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. MicroRNAs (miRNAs) are pivotal in modulating ferroptosis by targeting essential molecules, including SLC7A11, GPX4, ACSL4, FSP1, and several iron-handling proteins, thereby influencing cellular susceptibility to oxidative damage. Exercise-responsive miRNAs-encompassing both tissue-specific and circulating miRNAs-regulate angiogenesis, inflammation, mitochondrial biogenesis, metabolic homeostasis, and cellular stress responses. Recent research suggests that specific miRNAs, such as miR-124, miR-9, miR-23, and miR-378, are relevant to both exercise adaptation and ferroptosis. This indicates a potential molecular connection between improved muscular performance and the mitigation of excessive iron-induced oxidative stress. These overlapping miRNAs are hypothesized to enhance antioxidant defenses, regulate iron transport, and maintain mitochondrial function during repeated redox stressors, such as those encountered during strenuous physical activity. However, research gaps remain regarding tissue specificity, longitudinal alterations in miRNA expression, and the precise extent to which miRNAs promote cytoprotection against ferroptosis in exercised tissues. Future directions encompass comprehensive time-course research, interventional experiments utilizing miRNA mimics or antagomiRs, and clinical trials to substantiate the therapeutic potential of these interactions. Integrating core findings from ferroptosis research with exercise physiology may lead to innovative strategies to enhance oxidative resilience and reduce cell death across various illness scenarios.