The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System Xc −), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System Xc −/GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System Xc −/GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System Xc −/GSH/GPX4 axis in the treatment of drug-resistant solid tumors.

System Xc −/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

Selenoprotein GPX4 (glutathione peroxidase 4), originally known as PHGPX (phospholipid hydroperoxide glutathione peroxidase), is the main oxidoreductase in the use of glutathione as a reducing agent in scavenging lipid peroxidation products. There are three GPX4 isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct spatiotemporal expression patterns during embryonic development and adult life. In addition to inducing the main phenotype of ferroptosis, the loss of GPX4 can in some cells trigger apoptosis, necroptosis, pyroptosis, or parthanatos, which mediates or accelerates developmental defects, tissue damage, and sterile inflammation. The interaction of GPX4 with the autophagic degradation pathway further modulates cell fate in response to oxidative stress. Impaired GPX4 function is implicated in tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, and ischemia-reperfusion injury. Additionally, the R152H mutation in GPX4 can promote the development of Sedaghatian-type spinal metaphyseal dysplasia, a rare and fatal disease in newborns. Here, we discuss the roles of classical GPX4 functions as well as emerging GPX4-regulated processes in cell death, autophagy, and disease.Abbreviations: AA: arachidonic acid; cGPX4: cytosolic GPX4; CMA: chaperone-mediated autophagy; DAMPs: danger/damage-associated molecular patterns; mGPX4: mitochondrial GPX4; nGPX4: nuclear GPX4; GSDMD-N: N-terminal fragment of GSDMD; I/R: ischemia-reperfusion; PLOOH: phospholipid hydroperoxide; PUFAs: polyunsaturated fatty acids; RCD: regulated cell death; ROS: reactive oxygen species; Se: selenium; SSMD: Sedaghatian-type spondylometaphyseal dysplasia; UPS: ubiquitin-proteasome system.

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2023.2218764?needAccess=true&role=button

GPX4 in cell death, autophagy, and disease.

Identification of essential sites of lipid peroxidation in ferroptosis

Glutathione peroxidase 4 (GPx4) moonlights as structural protein and antioxidase that powerfully inhibits lipid oxidation. In the past years, it is considered as a key regulator of ferroptosis, which takes role in the lipid and amine acid metabolism and influences the cell aging, oncogenesis, and cell death. More and more evidences show that targeting GPX4-induced ferroptosis is a promising strategy for disease therapy, especially cancer treatment. In view of these, we generalize the function of GPX4 and regulatory mechanism between GPX4 and ferroptosis, discuss its roles in the disease pathology, and focus on the recent advances of disease therapeutic potential. 

GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment.

Ferroptosis and neuroinflammation play crucial roles in Alzheimer's disease (AD) pathophysiology. Forsythoside A (FA), the main constituent of Forsythia suspensa (Thunb.) Vahl., possesses anti-inflammatory, antibacterial, antioxidant, and neuroprotective properties. The present study aimed to investigate the potential role of FA in AD neuropathology using male APP/PS1 double transgenic AD mice, Aβ1-42-exposed N2a cells, erastin-stimulated HT22 cells, and LPS-induced BV2 cells. FA treatment significantly improved mitochondrial function and inhibited lipid peroxidation in Aβ1-42-exposed N2a cells. In LPS-stimulated BV2 cells, FA treatment decreased the formation of the pro-inflammatory factors IL-6, IL-1β, and NO. In male APP/PS1 mice, FA treatment ameliorated memory and cognitive impairments and suppressed Aβ deposition and p-tau levels in the brain. Analyses using proteomics, immunohistochemistry, ELISA, and western blot revealed that FA treatment significantly augmented dopaminergic signaling, inhibited iron deposition and lipid peroxidation, prevented the activation of IKK/IκB/NF-κB signaling, reduced the secretion of pro-inflammatory factors, and promoted the production of anti-inflammatory factors in the brain. FA treatment exerted anti-ferroptosis and anti-neuroinflammatory effects in erastin-stimulated HT22 cells, and the Nrf2/GPX4 axis played a key role in these effects. Collectively, these results demonstrate the protective effects of FA and highlight its therapeutic potential as a drug component for AD treatment.

/pdf/forsythoside-a-mitigates-alzheimer-s-like-pathology-by-lkj370er.pdf

Forsythoside A Mitigates Alzheimer's-like Pathology by Inhibiting Ferroptosis-mediated Neuroinflammation via Nrf2/GPX4 Axis Activation

Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, has been found to negatively regulate the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role of GSTZ1 in sorafenib-induced ferroptosis in HCC cell lines and determine the involved molecular mechanisms. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1 deficient cell viability and promoted ferroptosis, accompanied with ectopic increases of iron and lipid peroxides. An in vivo experiment showed that the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1−/− mice. In conclusion, GSTZ1 was significantly downregulated in sorafenib resistant hepatoma cells. GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. GSTZ1 deficiency was resistant to sorafenib-induced ferroptosis and is, therefore, a potential therapeutic approach for treating HCC by synergizing sorafenib and RSL3 to induce ferroptosis.

/pdf/gstz1-sensitizes-hepatocellular-carcinoma-cells-to-sorafenib-lfowbhxz42.pdf

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis

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GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis