Metabolic networks in ferroptosis (Review)

Abstract

Abstract.Ferroptosis is an iron-dependent and peroxidation-driven form of cell death associated with multiple metabolic disorders and disrupted homeostasis. A number of metabolic processes and homeostasis are affected by ferroptosis. The molecules that regulate ferroptosis are involved in metabolic pathways that regulate cysteine exploitation, glutathione state, nicotinamide adenine dinucleotide phosphate function, lipid peroxidation and iron homeostasis. The present review summarizes the metabolic networks involved in ferroptosis based on previous studies, and discusses the function of ferroptosis in pathological processes, including cancer. Finally, the clinical significance of ferroptosis is highlighted, to provide evidence for further studies.

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…GSH is a cofactor and a synthetic substrate for GPX4, and it is required for the lipid repair function of GPX4 (Feng and Stockwell, 2018). GSH is an essential intracellular antioxidant synthesized by glutamate, cysteine, and glycine, which is composed of ATP-dependent cytoplasmic enzymes glutamate-cysteine ligase (GCL) and GSH synthetase (GSS) and cystine/glutamate reverse transport system Xc-[or xCT/12 channel transmembrane protein transport protein carrier family 7 member 11 (SLC7A11) mediates the uptake of cystine to exchange the output of glutamate] was identified as the pivotal regulator for GSH synthesis (Hao et al, 2018). Inhibition of system Xc-led to the depletion of cysteine, lacking GSH synthetic substrate, and then impaired the function of antioxidant enzyme GPX4 (Friedmann Angeli et al, 2014;Yang et al, 2014), which finally caused an imbalance of homeostatic oxygen homeostasis, leading to ferroptosis (Dixon et al, 2012).…”

Ferroptosis in Cancer Cell Biology

“…Consequently, transferrin, which binds free ferric iron (Fe 3+ ) and shuttles it into cells, was shown to regulate ferroptosis [22]. Once Fe 3+ is imported, endosomal six-transmembrane epithelial antigen of prostate 3 (STEAP3) catalyses the reduction to divalent iron (Fe 2+ ) and releases it to the cellular labile iron pool through the divalent metal transporter 1 (DMT1) [23]. Interestingly, DMT1 has been shown to be up-regulated upon ferroptosis-induction [24].…”

Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis

“…GSS (GSH synthetase), GCLM [the modifier subunit of -glutamylcysteine ligase (GCL)], GCLC (the catalytic subunit of GCL), and/or GSR (GSH disulfide reductase) were also reduced in many TNBC cell lines upon JQ1 + BTZ treatment. GCL and GSS are two critical GSH biosynthesis enzymes in mammalian cells (36), whereas GSR catalyzes the reduction of GSH disulfide (GSSG) to GSH. The reduced expression of these enzymes in response to the JQ1 + BTZ combination is consistent with the decreased levels of cellular GSH (Fig.…”