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Specifically, free polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA) and adrenic acid (AdA) are first activated by acyl-CoA synthetase long-chain family member 4 (ACSL4) to form their acyl-CoA esters (AA-CoA and AdA-CoA)

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Since the discovery of the first xCT inhibitor erastin [80], derivatives like imidazole ketone erastin (IKE) was developed to improve solubility meanwhile introducing lysine-reactive ketone as a covalent warhead, thereby achieving nanomolar IC 50 [81,82]