Ferroptosis is an iron-catalysed form of regulated cell death, which is critically dependent on phospholipid peroxidation of cellular membranes. Ferrostatin 1 was one of the first synthetic radical-trapping antioxidants (RTAs) reported to block ferroptosis and it is widely used as reference compound. Ferroptosis has been linked to multiple diseases and the use of its inhibitors could have therapeutic potential. Although, novel biochemical pathways provide insights for different pharmacological targets, the use of lipophilic RTAs to block ferroptosis remains superior. In this Review, we provide a comprehensive overview of the different classes of ferroptosis inhibitors, focusing on endogenous and synthetic RTAs. A thorough analysis of their chemical, pharmacokinetic, and pharmacological properties and potential for in vivo use is provided.
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http://dx.doi.org/10.1016/j.tips.2023.08.012 | DOI Listing |
Mol Biol Rep
January 2025
Department of Orthopedic Surgery, Institute of Bone Tumor, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200092, China.
Recently, there has been burgeoning interest in the involvement of cholesterol metabolism in cancer. Squalene epoxidase (SQLE), as a critical rate-limiting enzyme in the cholesterol synthesis pathway, has garnered attention due to its overexpression in various cancer types, thereby significantly impacting tumor prognosis and resistance mechanisms. Firstly, SQLE contributes to unfavorable prognosis through diverse mechanisms, encompassing modulation of the PI3K/AKT signaling pathway, manipulation of the cancer microenvironment, and participation in ferroptosis.
View Article and Find Full Text PDFJ Med Chem
January 2025
Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province; Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province; Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
Thioredoxin reductase 1 (TrxR1) is an important therapeutic target for nonsmall cell lung cancer (NSCLC) treatment due to its overexpression in NSCLC cells. In this work, to address the deficiency that sesquiterpene lactone containing α-methylene-γ-lactone moiety was rapidly metabolized by endogenous nucleophiles, series of novel thioether derivatives were designed and synthesized based on a reactive oxygen species (ROS)-triggered prodrug strategy. Among them, prodrug exhibited potent cytotoxicity against NSCLC cells and better release rates in response to ROS.
View Article and Find Full Text PDFClin Transl Med
February 2025
The Second Department of Thoracic Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan Province, P.R. China.
To investigate the potential mechanisms underlying neutrophil extracellular traps (NETs) confer ferroptosis resistance and CD8(+) T cell inhibition in lung adenocarcinoma (LUAD). By the intravenous injection of LLC cells into the tail vein, a LUAD mouse model was created. Phorbol-12-myristate-13-acetate (PMA) stimulated neutrophils to facilitate NETs formation and combined with NETs inhibitor DNase I to explore NETs mechanism on LLC cell proliferation, migration, ferroptosis resistance, and CD8(+) T cell activity.
View Article and Find Full Text PDFFree Radic Biol Med
January 2025
Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, China; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei City, Anhui Province, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. Electronic address:
Hemorrhagic shock and reperfusion (HSR) is the main cause of death following trauma. Cognitive impairment may persist after successful resuscitation from hemorrhagic shock, but the mechanisms remain elusive. This study demonstrated the presence of ferroptosis in an in vitro model of oxygen-glucose deprivation and reoxygenation (OGD/R) in HT22 neurons, and also in a murine model of HSR using 3-month-old C57BL/6 mice.
View Article and Find Full Text PDFBioorg Chem
January 2025
Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Department of Urology and Department of Cancer Center of the Second Affiliated Hospital, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China; The Fifth People's Hospital of Shanghai, Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address:
Ferroptosis is a novel type of programmed cell death characterized by radical-driven lipid peroxidation accumulation, which is involved in various diseases, including acute organ injury and neurodegenerative disorders. Pharmacological inhibition of ferroptosis is a promising strategy for treating these diseases. In this study, 16 benzo[b][1,4]oxazine derivatives were synthesized and assayed for their antiferroptotic activity.
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