Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.

ABSTRACT: Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased the sensitivity to BSO and other ferroptosis-inducing agents, in a panel of mouse and human lung cancer cells, without affecting glutathione production. Activation of the amino ac

SUBMITTER: Garellick VA 

PROVIDER: S-EPMC12828773 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature