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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 X ), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System X /GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System X /GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System X /GSH/GPX4 axis in the treatment of drug-resistant solid tumors.
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http://dx.doi.org/10.3389/fphar.2022.910292 | DOI Listing |
Head Neck
August 2025
Department of Oncology and Institute of Medical Sciences, National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
Background: Radioresistance is a major problem in clinical treatment of nasopharyngeal carcinoma (NPC), and molecular mechanisms of radioresistance related to the antioxidant system are unknown. TXNIP (thioredoxin-interacting protein) is an endogenous inhibitor of thioredoxin. The system xCT/GSH/GPX4 axis is an important antioxidant system of ferroptosis in drug-resistant solid tumor therapy.
View Article and Find Full Text PDFFitoterapia
September 2025
Medical School, Linyi University, Linyi, Shandong, China. Electronic address:
Ferroptosis plays a crucial role in the development of diabetic kidney disease (DKD), and it is closely associated with oxidative stress. Low-molecular-weight fucoidan (LMWF) has been shown to exert an inhibitory action on oxidative stress. Herein, we investigated whether using LMWF to treat DKD is associated with ferroptosis and evaluated the action of LMWF on DKD using both in vivo and in vitro models.
View Article and Find Full Text PDFInt Immunopharmacol
July 2025
The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China. Electronic address:
Ischemic stroke is a cerebrovascular disease caused by the interruption of local blood flow in the brain. The mechanism of cerebral ischemia-reperfusion injury (CIRI) is complex and involves multiple pathological processes and signaling pathways. Ferroptosis, an iron-dependent regulated cell death form caused by excessive lipid peroxidation, is associated with the pathological occurrence and therapeutic response of various types of neurodegenerative diseases.
View Article and Find Full Text PDFJ Cell Mol Med
July 2025
Department of Medical Research, Mackay Memorial Hospital, New Taipei City, Taiwan.
Retinal pigment epithelial (RPE) cell damage caused by oxidative stress is a key factor in the pathogenesis of dry age-related macular degeneration (AMD). 6dS peptide is derived from the neuroprotective motif of pigment epithelium-derived factor (PEDF) and has antioxidant effects. This study used the sodium iodate (SI, a chemical oxidant)-induced animal dry AMD model to investigate the 6dS-mediated antioxidant mechanism.
View Article and Find Full Text PDFJ Clin Invest
July 2025
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America.
The cystine-xCT transporter-glutathione (GSH)-GPX4 axis is the canonical pathway protecting cells from ferroptosis. While GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Since cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system.
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