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.

Mitochondria-mediated ferroptosis contributes to the inflammatory responses of bovine viral diarrhea virus (BVDV) in vitro

“…GPX4 is the most critical ferroptosis defense gene that encodes cytosolic, mitochondrial, and nucleolar isoforms, whose functions include scavenging free radicals and detoxifying various xenobiotics and, consequently, converting itself to its oxidized form, GSSG ( 16 , 43 ). One of the key initial signals proposed to trigger ferroptosis is the inhibition of GPX4.…”

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

“…Selenocysteine, an essential amino acid in the GPX4 active group, relies on selenocysteine tRNA for insertion into GPX4. The mevalonate (MVA) pathway influences GPX4 synthesis by regulating selenocysteine tRNA maturation (Chen, Shi, et al, 2023). Isopentenyl pyrophosphate and coenzyme Q10 (CoQ10), products of the MVA pathway, are integral, and inhibiting this pathway downregulates selenocysteine tRNA synthesis, affecting GPX4 activity and inducing ferroptosis (Zhang et al, 2021).…”

Translational Potential of Baicalein in Mitigating RSL3-Induced Ferroptosis in Fibroblasts: Implications for Therapeutic Interventions

“…The gene expression of these factors can be influenced by various signaling pathways and transcriptional regulators involved in ferroptosis. These include nuclear factor erythroid 2-related factor 2 (Nrf2) 18 - 21 , the ferroptosis suppressor protein glutathione peroxidase 4 (GPX4) 22 - 24 , the tumor suppressor protein p53 25 - 27 , and System xc-, a cystine-glutamate antiporter consisting of solute carrier (SLC)3A2 and SLC7A11, which is crucial for importing cystine into the cell in exchange for glutamate 28 , 29 . The small-molecule compound rat sarcoma virus-selective lethal 3 (RSL3) is frequently employed as a ferroptosis activator, inhibits the function of GPX4, and causes a buildup of lipid peroxides, which initiates a chain reaction of lipid peroxidation.…”