Ferroptosis Regulation by the NGLY1/NFE2L1 Pathway

Abstract

Cells are equipped with various mechanisms to maintain cell viability upon exposure to stress. The Cap ‘n’ Collar (CNC) family includes five vertebrate stress‐responsive transcription factors. The CNC member nuclear factor erythroid 2 like 2 (NFE2L2) is considered the master regulator of the cellular oxidative stress response. Fellow CNC member nuclear erythroid 2 like 1 (NFE2L1) is better known for its role in responding to proteasome dysfunction. We hypothesized that NFE2L1 also responds to oxidative stress. We demonstrate that genetic disruption of NFE2L1 sensitizes cancer cells to death by a non‐apoptotic, oxidative form of cell death termed ferroptosis. We also show that genetic disruption of N‐glycanase 1 (NGLY1), which catalyzes NFE2L1 deglycosylation and sequence editing, sensitizes cancer cells to ferroptosis through an NFE2L1‐dependent mechanism. Expression of a sequence‐edited NFE2L1 mutant, which mimics NGLY1‐processed NFE2L1, rescues cellular resistance to ferroptosis in NFE2L1 gene‐disrupted cells. Finally, we provide evidence that the ferroptosis protection conferred by NFE2L1 is mediated by the expression of glutathione peroxidase 4 (GPX4). All together, our results highlight the role of NFE2L1 in ferroptosis resistance and implicate NFE2L1 and NGLY1 as potential targets for cancer therapy.