Oxidative cell death in cancer: mechanisms and therapeutic opportunities Oxidative cell death is a form of cell death triggered by excessive reactive oxygen species (ROS), which can lead to damage of cellular components such as lipids, proteins, and DNA. This process can manifest in various forms, including ferroptosis, apoptosis, necroptosis, pyroptosis, paraptosis, parthanatos, and oxeiptosis, each with distinct genetic, biochemical, and signaling characteristics. Targeting key antioxidant proteins, such as SLC7A11, GCLC, GPX4, TXN, and TXNRD, represents an emerging approach for inducing oxidative cell death in cancer cells. This review provides a comprehensive summary of recent progress, opportunities, and challenges in targeting oxidative cell death for cancer therapy. ROS are generated through various cellular processes, including mitochondrial electron transport chain, peroxisomes, NADPH oxidase, lipoxygenase, cyclooxygenases, and cytochrome P450s. ROS elimination is facilitated by antioxidant systems, including enzymatic antioxidants such as SOD, CAT, GPX, and the thioredoxin (TXN)-thioredoxin reductase (TXNRD) system, and non-enzymatic antioxidants such as glutathione (GSH), vitamins, selenium, and metabolites like bilirubin and melatonin. The transcription factor NRF2 is a pivotal regulator of the antioxidant system, orchestrating the expression of genes crucial to antioxidant defense mechanisms. The mechanisms of oxidative cell death involve various pathways, including ferroptosis, which is an iron-dependent form of cell death triggered by the accumulation of toxic lipids, especially lipid hydroperoxides. ROS-mediated lipid peroxidation is a hallmark of ferroptosis, and the production of mitochondrial ROS contributes to the propagation of lipid peroxidation, potentially leading to ferroptosis. The Lands' cycle involves the removal and addition of fatty acids to phospholipids, which regulates development, immunity, inflammation, and other cellular functions. The phospholipid acyl chain remodeling (Lands' cycle) is essential for facilitating ferroptosis through the enrichment of membranes with polyunsaturated fatty acids (PUFA). Apoptosis is an extensively studied form of RCD that is orchestrated through the activation of caspases, protein cleavage, and the formation of apoptotic bodies. Apoptotic pathways can be divided into two categories: extrinsic apoptotic pathways triggered by cell death receptors, and intrinsic apoptotic pathways involving dysfunctional mitochondria. ROS activity is closely related to apoptosis, with mitochondria serving as the primary intracellular source of ROS. ROS-induced apoptosis is also correlated with increased expression or activity of the tumor suppressor protein p53. Necroptosis is a regulated form of cell death orchestrated by the interplay of keyOxidative cell death in cancer: mechanisms and therapeutic opportunities Oxidative cell death is a form of cell death triggered by excessive reactive oxygen species (ROS), which can lead to damage of cellular components such as lipids, proteins, and DNA. This process can manifest in various forms, including ferroptosis, apoptosis, necroptosis, pyroptosis, paraptosis, parthanatos, and oxeiptosis, each with distinct genetic, biochemical, and signaling characteristics. Targeting key antioxidant proteins, such as SLC7A11, GCLC, GPX4, TXN, and TXNRD, represents an emerging approach for inducing oxidative cell death in cancer cells. This review provides a comprehensive summary of recent progress, opportunities, and challenges in targeting oxidative cell death for cancer therapy. ROS are generated through various cellular processes, including mitochondrial electron transport chain, peroxisomes, NADPH oxidase, lipoxygenase, cyclooxygenases, and cytochrome P450s. ROS elimination is facilitated by antioxidant systems, including enzymatic antioxidants such as SOD, CAT, GPX, and the thioredoxin (TXN)-thioredoxin reductase (TXNRD) system, and non-enzymatic antioxidants such as glutathione (GSH), vitamins, selenium, and metabolites like bilirubin and melatonin. The transcription factor NRF2 is a pivotal regulator of the antioxidant system, orchestrating the expression of genes crucial to antioxidant defense mechanisms. The mechanisms of oxidative cell death involve various pathways, including ferroptosis, which is an iron-dependent form of cell death triggered by the accumulation of toxic lipids, especially lipid hydroperoxides. ROS-mediated lipid peroxidation is a hallmark of ferroptosis, and the production of mitochondrial ROS contributes to the propagation of lipid peroxidation, potentially leading to ferroptosis. The Lands' cycle involves the removal and addition of fatty acids to phospholipids, which regulates development, immunity, inflammation, and other cellular functions. The phospholipid acyl chain remodeling (Lands' cycle) is essential for facilitating ferroptosis through the enrichment of membranes with polyunsaturated fatty acids (PUFA). Apoptosis is an extensively studied form of RCD that is orchestrated through the activation of caspases, protein cleavage, and the formation of apoptotic bodies. Apoptotic pathways can be divided into two categories: extrinsic apoptotic pathways triggered by cell death receptors, and intrinsic apoptotic pathways involving dysfunctional mitochondria. ROS activity is closely related to apoptosis, with mitochondria serving as the primary intracellular source of ROS. ROS-induced apoptosis is also correlated with increased expression or activity of the tumor suppressor protein p53. Necroptosis is a regulated form of cell death orchestrated by the interplay of key