Review suggests low-dose ozone pretreatment may enhance antioxidant systems and reduce inflammation in ischemia-reperfusion injuryLow-dose ozone pretreatment may protect cells from injury by boosting natural defenses

Ischemia-reperfusion (I/R) injury is a significant pathological phenomenon that affects the prognosis of various diseases in clinical settings, causing negative outcomes in multiple clinical conditions. Although early reperfusion after ischemia is crucial, it triggers excessive oxidative stress, inflammatory storm, ion imbalances, and various forms of programmed cell death, resulting in extensive tissue necrosis and severe functional damage. As a powerful oxidant, ozone exhibits paradoxical therapeutic effects when administered at controlled low doses. Low-dose ozone pretreatment targets multiple pathways to counteract major vicious cycles in ischemia-reperfusion injury. The protective effects of ozone primarily enhance cellular antioxidant systems (e.g., by upregulating SOD, HO-1, and GSH expression) and anti-inflammatory responses through activating the Nrf2 pathway. Concurrently, ozone reduces inflammation by inhibiting the TLR4/NF-κB signaling axis and regulates immune cell responses. Ozone inhibits key cell death pathways (including apoptosis, ferroptosis, pyroptosis, etc.) by altering caspase activity, Bcl-2/Bax ratios, and NLRP3 inflammasome activation, while enhancing mitochondrial protection. Moreover, the protective mechanisms of ozone against ischemia-reperfusion injury via pathways such as MAPK may represent another significant research direction. This review summarizes the protective effects of ozone against I/R injury across various organs and provides insights into the underlying mechanisms. Furthermore, we explore the potential clinical applications of ozone in the treatment of I/R injury. The studies outlined in this review provide theoretical support for the use of ozone in the treatment of I/R injury and offer new perspectives for clinical applications.