Fig. 4.

Targeting ferroptosis in reductive-oxidative pathways. Ferroptosis is tightly associated with levels of reactive oxygen species (ROS); therefore, homeostasis of the cellular reductive-oxidative response is important for regulating ferroptosis. The system Xc^–-GSH-GPX4 pathway is a major ROS scavenger, and numerous molecules are designed to target the components involved in this pathway in order to modulate ferroptosis. The recently identified FSP1-CoQ₁₀-NAD(P)H pathway and mitochondrial DHODH-mediated pathway are also potential targets for modulating ferroptosis. Moreover, NRF2 respond to cellular oxidative status by activating the transcription of genes involved in reductive-oxidative responses. Thus, targeting the KEAP1-NRF2 axis may be a viable strategy for modulating ferroptosis. Molecules listed in pink and green text boxes inhibit or induce, respectively, the indicated reductive-oxidative regulatory pathways, thereby suppressing or triggering, respectively, ferroptosis. CBS cystathionine beta-synthase, CoQ₁₀ coenzyme Q₁₀, CTH cystathionine gamma-lyase, DHODH dihydroorotate dehydrogenase, DPP4 dipeptidyl peptidase 4, FMN flavin mononucleotide, FMNH₂ reduced flavin mononucleotide, FSP1 ferroptosis suppressor protein 1, GCL glutamate-cysteine ligase, GLS glutaminase, GLUD1 glutamate dehydrogenase 1, GPX4 glutathione peroxidase 4, GSH glutathione, GSR glutathione disulfide reductase, GSS glutathione synthetase, GSSG glutathione disulfide, KEAP1 Kelch-like ECH-associated protein 1, NOX1 NADPH oxidase 1, NRF2 nuclear factor erythroid 2-related factor 2, SLC solute carrier family, TCA tricarboxylic acid, TXNRD thioredoxin reductase. Created with BioRender.com