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In this study, we reveal a cysteine-reactive covalent ligand EN25 that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, leading to inhibition of GCL activity, lowering of cellular GSH levels, and impaired cell viability in ARID1A-deficient cancer cells that are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells