Figure 1.

Inhibition of tRNA synthetases restores glutathione from the effects of cystine deprivation in ferroptosis. Ferroptosis-susceptible cells rely on cystine uptake as the primary source of cysteine. However, tRNA synthetase (ARS) inhibition can activate the transsulfuration pathway to synthesize cysteine. The dashed arrow indicates the hypothetical mechanism by which ATF4 activates the transsulfuration pathway through ARS inhibition. Compounds in green indicate ferroptosis inducers targeting different points. ARS, tRNA synthetase; ATF4, activating transcription factor 4; BSO, buthionine sulfoximine; Cys-Cys, cystine; GPX4, glutathione peroxidase 4; Met, methionine; Ser, serine.