Ischemia-reperfusion injury (I/R injury) is a critical condition that causes severe clinical manifestations, including myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. It occurs when blood flow is restored to ischemic tissue, leading to secondary injury due to increased local inflammation and reactive oxygen species (ROS) production. Cell damage from I/R injury can lead to apoptosis, autophagy, necrosis, and necroptosis. Understanding the mechanisms of I/R injury is essential for developing new therapeutic interventions. The mechanisms of I/R injury involve several pathways, including the NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system. These systems contribute to oxidative stress, which promotes endothelial dysfunction, DNA damage, and local inflammatory responses. ROS production is also involved in the activation of inflammatory cascades and cytokine storms, leading to cell death. Xanthine oxidase induces ROS production by oxidizing hypoxanthine to xanthine and xanthine to uric acid. This process generates superoxide and hydrogen peroxide, which contribute to oxidative stress and cell damage. NADPH oxidase produces ROS through the activation of HIF-1α, phospholipase A2, TNF-α, IL-1β, IFN-γ, and angiotensin II. ROS also contribute to the activation of inflammatory pathways and the formation of necrosomes, leading to cell death. NOS uncoupling produces ROS, which induces I/R injury and cell death. The balance of BH4 and NOS activity is crucial for NO production and the prevention of oxidative stress. Oxidative stress can also lead to the uncoupling of NOS, resulting in increased ROS production and cell damage. Cell death in I/R injury can occur through apoptosis, mitoptosis, necrosis, and necroptosis. Apoptosis is regulated by the extrinsic and intrinsic pathways, involving caspase activation and mitochondrial dysfunction. Mitoptosis involves the fragmentation of mitochondria and the formation of BAX/Drp1 oligomers. Necrosis and necroptosis are characterized by cell membrane permeation and organelle swelling, with necroptosis being a form of programmed cell death controlled by death signals. Autophagy is a cellular process that degrades damaged organelles and macromolecules. It is regulated by autophagy-related proteins and pathways such as mTOR, PI3K-Akt, p53, and AMPK. Autophagy can be induced during I/R injury and may help in clearing dysfunctional mitochondria, but excessive autophagy can lead to mitochondrial permeability transition and cell death. Therapeutic approaches for I/R injury include the use of NO-based strategies, nuclear transcription factors, and calcium overload protection measures. These approaches aim to reduce ROS productionIschemia-reperfusion injury (I/R injury) is a critical condition that causes severe clinical manifestations, including myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. It occurs when blood flow is restored to ischemic tissue, leading to secondary injury due to increased local inflammation and reactive oxygen species (ROS) production. Cell damage from I/R injury can lead to apoptosis, autophagy, necrosis, and necroptosis. Understanding the mechanisms of I/R injury is essential for developing new therapeutic interventions. The mechanisms of I/R injury involve several pathways, including the NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system. These systems contribute to oxidative stress, which promotes endothelial dysfunction, DNA damage, and local inflammatory responses. ROS production is also involved in the activation of inflammatory cascades and cytokine storms, leading to cell death. Xanthine oxidase induces ROS production by oxidizing hypoxanthine to xanthine and xanthine to uric acid. This process generates superoxide and hydrogen peroxide, which contribute to oxidative stress and cell damage. NADPH oxidase produces ROS through the activation of HIF-1α, phospholipase A2, TNF-α, IL-1β, IFN-γ, and angiotensin II. ROS also contribute to the activation of inflammatory pathways and the formation of necrosomes, leading to cell death. NOS uncoupling produces ROS, which induces I/R injury and cell death. The balance of BH4 and NOS activity is crucial for NO production and the prevention of oxidative stress. Oxidative stress can also lead to the uncoupling of NOS, resulting in increased ROS production and cell damage. Cell death in I/R injury can occur through apoptosis, mitoptosis, necrosis, and necroptosis. Apoptosis is regulated by the extrinsic and intrinsic pathways, involving caspase activation and mitochondrial dysfunction. Mitoptosis involves the fragmentation of mitochondria and the formation of BAX/Drp1 oligomers. Necrosis and necroptosis are characterized by cell membrane permeation and organelle swelling, with necroptosis being a form of programmed cell death controlled by death signals. Autophagy is a cellular process that degrades damaged organelles and macromolecules. It is regulated by autophagy-related proteins and pathways such as mTOR, PI3K-Akt, p53, and AMPK. Autophagy can be induced during I/R injury and may help in clearing dysfunctional mitochondria, but excessive autophagy can lead to mitochondrial permeability transition and cell death. Therapeutic approaches for I/R injury include the use of NO-based strategies, nuclear transcription factors, and calcium overload protection measures. These approaches aim to reduce ROS production