ABSTRACT
This chapter aims to provide a historical appraisal of the initial findings linking thiol metabolism with particular emphasis on its support to glutathione (GSH) biosynthesis, culminating in proper activity of what is now known to be the rate-limiting enzyme in providing the prosurvival function of GSH, glutathione peroxidase 4 (GPx4). The viability of hepatocytes lacking xCT is accompanied by an increased consumption of methionine, a feature consistent with observations showing that the transsulfuration pathway is able to sustain the cysteine pool. The identification of GPx4 as the limiting factor in the prosurvival function conferred by GSH in tissues and cells combined with the development of pharmacological and genetic tools provided the ideal framework to understand the factors dictating sensitivity to this form of cell death. The first indications that ferroptosis could be involved in pathological setting came from the findings that Gpx4 conditional knockout animals presented delayed mortality, when treated with the ferroptosis inhibitor liproxstatin-1.
