Sweat, Y. Y. | bioRxiv Science

bioRxiv2024

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

Despite glutathiones 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.

cancer biology↗

bioRxiv2024

Commonly used organoid culture media prevent ferroptosis

Organoids enable the recreation of organ physiology in vitro and serve as powerful models for biology in basic life science research and drug discovery and development. However, organoid culture requires complex media formulations that include antioxidants, potentially confounding experimental results sensitive to such conditions. Here we report that the growth conditions used commonly to generate organoid models inhibit ferroptosis, an iron-dependent form of lipid peroxidative cell death with relevance to human disease, thus rendering such models incompatible with ferroptosis research. We identify medium components that diminish or eliminate ferroptosis sensitivity and outline strategies for avoiding anti-ferroptotic culture conditions in organoid and other cell culture applications. These findings provide a roadmap for adapting organoid models for the study of ferroptosis and leveraging their strengths for advancing ferroptosis-modulating therapeutics.

cancer biology↗