Cyclophosphamide-induced GPX4 degradation triggers parthanatos by activating AIFM1

Cyclophosphamide is an alkylating agent used to treat a variety of cancers, including leukemia. Here, we show a previously unrecognized role of cyclophosphamide in triggering the protein degradation of glutathione peroxidase 4 (GPX4), a phospholipid hydroperoxidase that protects cells from oxidative damage. Mechanistically, we found that the ubiquitin-proteasome system, but not autophagy, mediates cyclophosphamide-induced degradation of GPX4 in human leukemia cell lines. Surprisingly, cyclophosphamide-induced degradation of GPX4 leads to caspase-independent parthanatos, but not lipid peroxidation-mediated ferroptosis, through the nuclear translocation of apoptosis-inducing factor mitochondria-associated 1 (AIFM1). Consequently, the overexpression of GPX4 or the knockdown of AIFM1 limits the anticancer activity of cyclophosphamide in vitro and in xenograft tumor models. These findings establish a new framework for understanding the central role of GPX4 in blocking oxidative cell death.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

Cyclophosphamide triggers the degradation of GPX4 to block oxidative cell death by utilizing the ubiquitin-proteasome system. This study reveals the mechanism of cyclophosphamide-induced GPX4 degradation and highlights the significant role of AIFM1 in this process.