Fig. 4: The role of ROS in necroptosis.
From: Oxidative cell death in cancer: mechanisms and therapeutic opportunities
Necroptosis is a regulated cell death orchestrated by receptor-interacting serine/threonine kinase 1 (RIPK1), receptor-interacting serine/threonine kinase 3 (RIPK3), and mixed lineage kinase domain-like pseudokinase (MLKL). Activation of receptors (e.g., TNFR1, TLR3, TLR4, and IFNAR1) prompts the recruitment of RHIM-containing proteins like RIPK1, TRIF, and ZBP1, and subsequent necrosome on the cytoplasmic side. Necroptosis is suppressed by caspase 8 (CASP8), and simultaneous treatment with TNF and caspase inhibitors can activate it. Subsequently, necrosomes form involving RIPK3 and MLKL in response to activation cues, which drives MLKL phosphorylation, oligomerization, and translocation to the plasma membrane for pore formation. ROS triggers RIPK1 autophosphorylation and MLKL activation. RIPK3 can also elevate ROS by stimulating mitochondrial metabolism and NADPH oxidase (NOX) activity. It enhances energy metabolism and mitochondrial ROS production through interactions with metabolic enzymes like pyruvate dehydrogenase complex (PDH), glutamate-ammonia ligase (GLUL), glutamate dehydrogenase 1 (GLUD1), and glycogen phosphorylase L (PYGL). Conversely, NRF2 induces transcription of antioxidant genes, mitigating ROS and ameliorating necroptosis.
