Fig. 5
Schematic representation of the effect of DHODH knockdown on ferroptosis-mediated radiosensitivity caused by SOD2 depletion. When both SOD2 and DHODH are fully active, Ci and Ciii of the ETC generate O2.−. SOD2 converts the O2.− to H2O2 which is converted to H2O by catalase, peroxidases, or thioredoxins. This results in ferroptosis inhibition. When only SOD2 is deficient, the Warburg effect inhibits Ci and Cii, hence only Ciii generate O2.−. Under this condition, O2.− accumulates and ferroptosis is induced thereby enhancing radiosensitivity. When both SOD2 and DHODH are depleted, the Warburg effect inhibits Ci and Cii, and DHODH does not facilitate the generation of O2.− by Ciii. Therefore, no O2.− is produced by the ETC. This inhibits ferroptosis and radiosensitivity. *Ci = Complex I; Cii = Complex II; Ciii = Complex = III; Civ = Complex IV; 1 = SOD2; 2 = Catalase, Peroxidases or Thioredoxins; ETC = Electron Transport Chain