Figure 1.

Induction of ferroptosis by FIN56. FIN56 promotes ferroptosis by two distinct mechanisms: (i) negative regulation of GPX4 protein levels and (ii) activation of squalene synthase (SQS), which acts downstream of HMG-CoA reductase in the mevalonate pathway. In one mechanism (purple boxes), FIN56 promotes degradation of GPX4 in a process that requires acetyl-CoA carboxylase (ACC) activity. Inhibition of ACC by TOFA suppresses the FIN56-mediated degradation of GPX4, yet the link between FIN56, ACC and GPX4 degradation is not clear (gray dashed arrows). In the second mechanism (blue boxes), FIN56 binds and activates SQS, the enzyme that converts farnesyl pyrophosphate (FPP) to squalene, which ultimately reduces the pool of FPP available for protein prenylation and metabolite synthesis, leading to coenzyme Q₁₀ (CoQ₁₀) depletion, for example (black arrows). Inhibition of SQS increases the pool of available FPP and its derived products, suppressing ferroptosis. GPX4, glutathione peroxidase 4; TOFA, 5-(tetradecyloxy)-2-furoic acid; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A.