Beyond Paradox: Ozone Therapy as a Hormetic Modulator in Ischemia-Reperfusion Injury - An Update

Ischemia-reperfusion injury (IRI) represents a significant clinical challenge characterized by mitochondrial dysfunction and redox imbalance during blood flow restoration following ischemia. This review provides a critical analysis of ozone therapy's emerging role in IRI management through its unique hormetic properties. Recent research has transformed our understanding of ozone-traditionally considered harmful-revealing that controlled administration demonstrates remarkable therapeutic potential through dose-dependent effects. Quantitative analysis reveals that low-dose ozone exposure (10-40 µg/mL) significantly reduces oxidative stress markers while increasing antioxidant enzyme activity across multiple organ systems. The protective effects manifest primarily through enhanced Nuclear factor erythroid 2-related factor 2 activity, orchestrating upregulation of key protective enzymes while suppressing excessive nuclear factor kappa B mediated inflammation. Current evidence demonstrates consistent protective effects across cardiovascular, digestive, urogenital, and cerebral systems, with effect sizes ranging from moderate to large. However, critical analysis reveals significant limitations including predominant reliance on animal models (>95% of studies), lack of standardized protocols, and limited human clinical data. Safety assessment indicates a narrow therapeutic window, with beneficial effects observed at 10-40 µg/mL but potential toxicity at doses >80 µg/mL. This review establishes that while ozone therapy shows promising experimental efficacy in IRI through hormetic modulation of cellular stress responses, substantial research gaps exist regarding optimal dosing, administration protocols, and long-term safety. Future clinical translation requires rigorous standardization of therapeutic parameters, comprehensive safety assessment, and well-designed human trials to validate experimental findings.