Understanding the Regulation of Ferroptosis

Small molecules can be used to activate or inhibit protein function and thereby discover and study novel cellular phenotypes.  The small molecule named erastin triggers a novel cell death phenotype called ferroptosis.  Ferroptosis requires iron and reactive oxygen species production and is morphologically, biochemically and genetically distinct from apoptosis, programmed necrosis and autophagy-associated death.  This pathway may be selectively activated by erastin and related molecules in certain RAS pathway-mutant tumors and may also be relevant to cell death during glutamate-induced neurodegeneration in the brain.  Our current understanding of the ferroptotic pathway is outlined below.

  A working model of the ferroptotic pathway.  Erastin somehow inhibits the function of the system xc- cystine/glutamate transporter.  This in turn results in the depletion of intracellular cysteine.  Cysteine is rate-limiting for the synthesis of reduced glutathione (GSH), a key intracellular antioxidant molecule.  Thus, inhibition of system xc- eventually leads to the depletion of GSH and the iron-dependent accumulation of toxic lipid ROS.

A working model of the ferroptotic pathway.  Erastin somehow inhibits the function of the system xc- cystine/glutamate transporter.  This in turn results in the depletion of intracellular cysteine.  Cysteine is rate-limiting for the synthesis of reduced glutathione (GSH), a key intracellular antioxidant molecule.  Thus, inhibition of system xc- eventually leads to the depletion of GSH and the iron-dependent accumulation of toxic lipid ROS.