The fruitfly Drosophila melanogaster as an in vivo model of ferroptosis.

Ferroptosis is an iron-dependent form of cell death involved in cancer, ischemia-reperfusion injury, inflammation, and neurodegeneration. It can be triggered in two ways: class 1 inhibitors such as erastin block system xc, the cystine/glutamate antiporter composed of xCT and 4F2hc/CD98, causing glutathione depletion, whereas class 2 inhibitors such as RSL3 directly inhibit glutathione peroxidase 4, causing lipid peroxidation. Ferroptotic cell death is suppressed by radical-trapping antioxidants like ferrostatin-1. We investigated the effects of erastin and RSL3 on Drosophila melanogaster lifespan, iron metabolism, and lipid composition. Erastin and RSL3 dose- and diet-dependently shortened lifespan which was rescued by ferrostatin-1. Erastin increased the Fe/Fe ratio and reduced ferritin-bound iron, and RSL3 remodeled lipid composition consistent with lipid peroxidation. Both effects occurred only in male w flies although both sexes had similarly reduced lifespans. Total glutathione was unchanged by erastin; notably, the fly GPX4 ortholog Gtpx is a non-selenocysteine, thioredoxin-dependent peroxidase. Complete Gtpx knockout caused early lethality mirroring the embryonic lethality of constitutive GPX4 knockout in mice but was not affected by ferrostatin-1. Flies also lack a clearly defined xCT ortholog. Together, these results establish male w flies as a suitable in vivo ferroptosis model and point to glutathione-independent actions of erastin.

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PMID: 42822391