tRNA synthase suppression activatesde novocysteine synthesis to compensate for cystine and glutathione deprivation during ferroptosis

Metabolic networks in ferroptosis (Review)

“…In the 1970s, deprivation of Cys2 was revealed to lead to marked depletion of GSH and the promotion of cell death (3,33), suggesting that cysteine uptake may be the limiting factor for GSH biosynthesis. Several subsequent pharmacological studies of glutamate-or erastin-induced ferroptosis further demonstrated that decreased GSH levels triggered by cysteine deprivation may induce the initiation of oxidative stress and ferroptotic cell death (2,3,7,15,20,28). GSH biosynthesis is critical for protecting cells from oxidative damage, and the cysteine-GSH pathway is one of the most pivotal upstream mechanisms for the execution of ferroptosis.…”

“…Acting as a glutamate-cystine antiporter, inhibition of the Xc -system may lead to depletion of the intracellular cysteine pool, one of the molecular events that induces ferroptosis (2,7,21,28). As a classic inducer of ferroptosis, erastin suppresses the glutamate-cystine antiporter (21).…”

“…GPX uses the thiol group in GSH as an electron donor and affects the cellular antioxidant reaction (15,28). Inactivation of GPX4 induced by GSH depletion increases intracellular lipid peroxides, resulting in ferroptosis (10,15).…”

“…1). Genome-wide siRNA screening has revealed that silencing of cysteinyl tRNA synthetase (CARS) suppresses erastin-induced ferroptosis (10,28). CBS and CGL are upregulated in CARS-deprieved cells, and metabolites accumulate in the trans-sulfuration pathway following erastin treatment (6,10,32).…”

“…Cellular cysteine is primarily obtained by extracellular cysteine uptake through the glutamate/cysteine antiporter (Xc -) (6,27,28). In addition to extracellular uptake, certain mammalian cells are able to use methionine as a sulfur donor to synthesize de novo cysteine through the trans-sulfuration pathway (6,(28)(29)(30).…”