Examining the Impact of PUFAs and the Role of Autophagy in Iron-Induced Ferroptotic Cell Death

Ferroptosis, an iron-dependent non-apoptotic cell death involves lipid peroxidation and associates with cardiometabolic disease and cancer. I established a model of iron overload in L6 cells and measured cell viability, toxicity and lipid peroxidation. Importantly, in PUFA pre-treated cells, the susceptibility to iron-induced lipid peroxidation was enhanced. This resulted in ferroptosis as cell death was attenuated by ferrostatin-1, a ferroptosis inhibitor, yet no attenuation was seen when an inhibitor of apoptosis was used. Increased lipid peroxidation was also found in PUFA pre-treaded cells in wild type but not in autophagy deficient cells. Additionally, preliminary data indicated an apparent rescue of ferroptosis-induced cell death when using the adiponectin receptor agonist ALY688, an autophagy inducer. In conclusion, these findings supported the theory that PUFAs can alter the cell susceptibility to iron-induced ferroptotic cell death and raise the possibility that autophagy plays a protective role against ferroptosis.