Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation

Cell Death Differ. 2016 Feb;23(2):270-8. doi: 10.1038/cdd.2015.93. Epub 2015 Jul 17.


Ferroptosis is a form of regulated non-apoptotic cell death that has been implicated in several disease contexts. A better understanding of the ferroptotic death mechanism could lead to the development of new therapeutics for degenerative diseases, and a better understanding of how to induce ferroptosis in specific tumor contexts. We performed an unbiased genome-wide siRNA screen to find genetic suppressors of ferroptosis. We determined that loss of CARS, the cysteinyl-tRNA synthetase, suppresses ferroptosis induced by erastin, which inhibits the cystine-glutamate antiporter known as system xc(-). Knockdown of CARS inhibited erastin-induced death by preventing the induction of lipid reactive oxygen species, without altering iron homeostasis. Knockdown of CARS led to the accumulation of cystathionine, a metabolite on the transsulfuration pathway, and upregulated genes associated with serine biosynthesis and transsulfuration. In addition, inhibition of the transsulfuration pathway resensitized cells to erastin, even after CARS knockdown. These studies demonstrate a new mechanism of resistance to ferroptosis and may lead to strategies for inducing and suppressing ferroptosis in diverse contexts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acyl-tRNA Synthetases / genetics*
  • Amino Acyl-tRNA Synthetases / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Biosynthetic Pathways
  • Cystine / metabolism
  • Drug Resistance, Neoplasm
  • Gene Knockdown Techniques
  • Glutamic Acid / pharmacology
  • Humans
  • PC12 Cells
  • Piperazines / pharmacology
  • Rats
  • Reactive Oxygen Species / metabolism
  • Serine / biosynthesis
  • Signal Transduction


  • Antineoplastic Agents
  • Piperazines
  • Reactive Oxygen Species
  • erastin
  • Glutamic Acid
  • Serine
  • Cystine
  • Amino Acyl-tRNA Synthetases
  • cysteinyl-tRNA synthetase