The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer

Abstract Despite glutathione’s long-recognized role as a major cellular antioxidant and its central role in ferroptosis defense, inhibition of glutathione biosynthetic enzymes has received little attention as a target for the therapeutic induction of ferroptosis. Here, we report that small-molecule inhibition of glutamate–cysteine ligase (GCL), the rate-limiting enzyme of glutathione biosynthesis, selectively and potently kills cancer cells by ferroptosis. We further describe novel GCL inhibitors including KOJ-1 and KOJ-2, compounds with excellent cellular potency and pharmacological properties, representing valuable tools to study the biology of ferroptosis and glutathione. Competing Interest Statement V.S.V is a co-founder and equity holder of Kojin Therapeutics. All authors are equity holders of Kojin Therapeutics and are either current or past employees of Kojin Therapeutics. J.K.E, L.F., J.H.J. and V.S.V. are inventors of patents related to ferroptosis and GCL.