Prospects for Anti-Tumor Mechanism and Potential Clinical Application Based on Glutathione Peroxidase 4 Mediated Ferroptosis

Abstract

Ferroptosis, characterized by excessive iron accumulation and lipid peroxidation, is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other known cell death types, such as apoptosis, necrosis, and autophagy. Emerging evidence shows that glutathione peroxidase 4 (GPX4), a critical core regulator of ferroptosis, plays an essential role in protecting cells from ferroptosis by removing the product of iron-dependent lipid peroxidation. The fast-growing studies on ferroptosis in cancer have boosted a perspective on its use in cancer therapeutics. In addition, significant progress has been made in researching and developing tumor therapeutic drugs targeting GPX4 based on ferroptosis, especially in acquired drug resistance. Selenium modulates GPX4-mediated ferroptosis, and its existing form, selenocysteine (Sec), is the active center of GPX4. This review explored the structure and function of GPX4, with the overarching goal of revealing its mechanism and potential application in tumor therapy through regulating ferroptosis. A deeper understanding of the mechanism and application of GPX4-mediated ferroptosis in cancer therapy will provide new strategies for the research and development of antitumor drugs.

Keywords: anti-tumor; cancer; ferroptosis; glutathione peroxidase 4; selenocysteine.

Figure 1

The ferroptosis regulatory pathway correlated to GPX4. Under oxidative conditions, the most upstream event of ferroptosis is the importation of Cys2 via system XC-. Cys2 is then reduced to Cys, which the system ASC can directly take under reduced conditions after it has been imported. In addition, there is another source of intracellular Cys in which Met is converted into Cys through the transsulfuration pathway. GSH, a vital antioxidant, is created by Cys, Glu, and Gly under two catalysis steps involving GCL and GSS cytosolic enzymes. GPX4 accepts electrons from GSH molecules, which reduces the toxic PE-AA-OOH/PE-AdA-OOH into nontoxic PE-AA-OH/PE-AdA-OH, ultimately inhibiting ferroptosis. GSH, the electron donor, is oxidized to GSSG that is then reduced to GSH by NADPH under the reductase GSR. Abbreviations: Gln, glutamine; GLS, glutaminase; Se, selenium; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; IPP, isopentenyl pyrophosphate; NADP+, nicotinamide adenine dinucleotide phosphate; PE-OOH, phosphatidyl-ethanolamine hydroperoxide; PE-OH, phosphatidyl-ethanolamine hydroxide.

Figure 2

Structures of GPX4-related molecules mentioned in the article. (A) (1S-3R)-RSL3, or RSL3, the first described Class II inhibitor that directly targets GPX4 to trigger ferroptosis. (B) (1R-3R)-RSL3, a diastereomer of (1S-3R)-RSL3, which loses its HRAS selectivity. (C,D) ML162 and ML 210, the direct GPX4 inhibitors. (E) FIN56, a Class III ferroptosis inducer, mainly triggers ferroptosis through cellular depletion of GPX4. (F,G) FINO2, a Class IV inducer that does not directly inhibit GPX4. (H) Erastin, a classic Class I inducer that function by inhibiting system x_c⁻ instead of affecting GPX4 directly.