Ferroptosis in cancer: metabolism, mechanisms and therapeutic prospects

Abstract

Ferroptosis is a form of cell death, distinct from apoptosis, necrosis and autophagy. It is a novel programmed cell death (PCD) triggered by iron accumulation and peroxidation associated with intracellular iron metabolism disorders. Since its naming in 2012, ferroptosis has garnered increasing attention for its role in human diseases, particularly in tumor formation, progression and therapy. Numerous studies have demonstrated that ferroptosis plays a crucial role in killing tumor cells, inhibiting tumor proliferation and metastasis and reversing therapy resistance. Consequently, targeted induction of ferroptosis in tumor cells holds promise as a novel antitumor therapeutic strategy.

Keywords: Cell death; Ferroptosis; Therapy resistance; Tumor.

Fig. 1

Metabolism in Ferroptosis. Intracellular iron metabolism disorders and abnormal lipid metabolism are the primary causes of ferroptosis. Fe³⁺ in plasma binds to Tf and enters cells via TfR1-mediated endocytosis. In endosomes, Fe³⁺ is released, reduced to Fe²⁺, and transported to the cytoplasm by DMT1. Intracellular iron overload induces fatty acid peroxidation via enzyme-dependent ROS generation and Fenton reaction-mediated free radicals. In fatty acid anabolism, PUFAs generated by ACSL4/LPCAT3 are more susceptible to lipid peroxidation under oxygen free radicals. In addition, redox imbalance in the body, triggered by dysregulated metabolism of amino acids like cysteine and glutamine, also serves as a contributing factor to its occurrence. System Xc⁻ takes up extracellular cystine and releases intracellular glutamate. Cystine is reduced to cysteine, which is catalyzed by GCL/GS to synthesize GSH (inhibits lipid peroxidation). In this pathway, CDO1 competitively binds cysteine with GCL to synthesize taurine, diverting cysteine from GSH synthesis and reducing intracellular GSH. Glutamine is an important carbon source in tumor cells. Cells acquire glutamine mainly through plasma membrane glutamine transporters and transport it to the mitochondrial matrix via SLC1A5, which is converted to glutamate by GLS. Glutamate is either converted to AKG (for tricarboxylic acid cycle intermediates, lipids, reducing equivalents) or provides amine nitrogen for serine/alanine synthesis; serine/alanine form glycine, which promotes cysteine synthesis via one-carbon metabolism. Tf: transferrin, TfR1:transferrin receptor 1, STEAP3: Six-Transmembrane Epithelial Antigen of the Prostate 3, DMT1: divalent metal transporter 1, FAs: fatty acids, ACSL3: acyl-CoA synthetase 3, ACSL4: acyl-CoA synthetase 4, LPCAT3: lysophosphatidylcholine acyltransferase 3, SCD: stearoyl-CoA desaturase, PUFA: polyunsaturated FA, MUFA: monounsaturated FA, GCL: glutamate-cysteine ligase, GGC: γ-glutamyl cysteine, GS: glutathione synthase, GSH: glutathione, CDO1: cysteine dioxygenase 1, GLS: glutaminase, AKG: α-ketoglutaric acid, NADPH: reduced nicotinamide adenine dinucleotide phosphate

Fig. 2

Ferroptosis regulation mechanisms. Iron-dependent accumulation of lipid oxygen free radicals is the primary driver of ferroptosis, and currently, there are three mechanisms targeting this process: the system Xc⁻, GSH-GPX4 pathway and the ferroptosis suppressor protein 1 (FSP1). (1) System Xc⁻ is a sodium-independent cystine/glutamate antiporter that uptakes extracellular cystine in a 1:1 ratio and exchange glutamate out of cells. The cystine from uptake is reduced to cysteine and participates in the synthesis of GSH; (2) GPX4, as a selenoprotein antioxidant enzyme, oxidizes GSH to GSSG and reduces toxic L-OOH to non-toxic L-OH, to control the diffusion of lipid peroxides and maintain membrane stability. (3) FSP1 can reduce CoQ10 and VK to CoQ10H2 and VKH2 respectively through the action of NADH/NADPH-dependent reductases, and CoQ10H2 and VKH2 can play an anti-lipid oxidation role. FSP1 can also repair damaged cell membranes by enhancing the function of the ESCRT-III complex, so as to prevent cells from dying due to iron-dependent lipid oxidation. In addition, NRF2 is a key transcription factor for maintaining cellular homeostasis, it interacts with antioxidant response elements (ARE) and activates the expression of antioxidative (such as HO-1) and metabolic regulatory genes (such as SCL7A11, GPX4 and FSP1). HO-1 can metabolize heme to Fe2 + and biliverdin. Increased expression and activity of HO-1 will increase the level of free iron. Excessive free iron can catalyze the generation of ROS and trigger lipid peroxidation. More importantly, as an antioxidant, biliverdin can resist the process of cell membrane lipid peroxidation. GSH: glutathione; GSSG: L-glutathione disulfide; GPX4: glutathione peroxidase 4; L-OH: lipid alcohols; L-OOH: lipid hydroperoxides; LOO: lipid peroxyl radical; FSP1: ferroptosis suppressor protein 1; VK: vitamin K; VKH2: vitamin K hydroquinone; ESCRT: endosomal sorting complex required for transport; ARE: Antioxidant Response Element; HO-1: Heme Oxygenase-1