Oxytosis pathway

Oxytosis is a form of regulated oxidative cell death primarily characterized by the depletion of intracellular glutathione (GSH) and the subsequent accumulation of reactive oxygen species (ROS) [1]. It is typically triggered by the inhibition of the cystine/glutamate antiporter (System xc-), which prevents the uptake of cystine required for GSH synthesis [2]. This pathway is closely related to, and often considered synonymous with, ferroptosis, although oxytosis was historically defined in the context of glutamate-induced toxicity in neuronal cells [3]. Key biochemical hallmarks include the activation of lipoxygenases, mitochondrial dysfunction, and a terminal influx of extracellular calcium that precedes cell death [4]. Oxytosis plays a significant role in the pathogenesis of various neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, as well as acute injuries like stroke and traumatic brain injury [1, 5]. Therapeutic strategies targeting this pathway focus on restoring GSH levels, inhibiting lipid peroxidation with lipophilic antioxidants, or blocking downstream signaling events such as calcium entry [2, 6].

Other names

Oxidative glutamate toxicityGlutamate-induced oxidative stressOxytosis

The pathway is initiated by the inhibition of the cystine/glutamate antiporter (System xc-), leading to the depletion of intracellular glutathione (GSH). This loss of antioxidant capacity results in the accumulation of reactive oxygen species (ROS), activation of lipoxygenases, and subsequent lipid peroxidation, ultimately leading to mitochondrial dysfunction and calcium-mediated cell death [1, 2].