Explore the vast range of titles available.

The selenoprotein glutathione peroxidase 4 (GPX4) is one of the main antioxidant mediators in the human body. Its central function involves the reduction of complex hydroperoxides into their respective alcohols often using reduced Glutathione (GSH) as a reducing agent. GPX4 has become a hotspot therapeutic target in biomedical research following its characterization as a chief regulator of ferroptosis, and its subsequent recognition as a specific pharmacological target for the treatment of an extensive variety of human diseases including cancers and neurodegenerative disorders. Several recent studies have provided insights into how GPX4 is distinguished from the rest of the glutathione peroxidase family, the unique biochemical properties of GPX4, how GPX4 is related to lipid peroxidation and ferroptosis, and how the enzyme may be modulated as a potential therapeutic target. This current report aims to review the literature underlying all these insights and present an up-to-date perspective on the current understanding of GPX4 as a potential therapeutic target.

Ferroptosis, a recently unveiled iron-dependent form of cellular demise, has emerged as a pivotal process contributing to the pathology of Alzheimer's Disease (AD). Glutathione Peroxidase 4 (GPX4), a vital defense mechanism countering ferroptosis by nullifying lipid peroxides and maintaining cellular redox equilibrium, has garnered significant attention in AD. Thus, identifying ferroptosis inhibitors to target GPX4 activation may help mitigate neuronal damage and impede AD progression. We aimed to screen potent ferroptosis inhibitors and investigate their mechanism of action and therapeutic potential in AD, as well as lay the groundwork for future research in this promising area of study. This study employed a natural compound library to screen potential ferroptosis inhibitors in RAS-selective lethal compounds 3 (RSL-3)-induced PC-12 cells. Ferroptosis was evaluated by examining the mitochondrial morphology and function, reactive oxygen species (ROS) production, and lipid peroxide levels. The ability to chelate iron and intracellular iron levels was determined by UHPLC-Q/TOF-MS/MS and PGSK staining, respectively. APP Swe/ind- or Tau P301L-overexpressing PC-12 cells, and Amyloid-β transgenic CL4176 and Tau transgenic BR5270 were employed as cellular and animal models of AD. Thonningianin A (ThA) was identified as a novel ferroptosis inhibitor, as demonstrated by augmented cellular viability, mitigated mitochondrial impairment, diminished lipid peroxides, iron levels, and ROS generation. Mechanistically, ThA binds with GPX4 and enhances the AMPK/Nrf2 signaling pathway to stimulate GPX4 activation, effectively inhibiting ferroptosis. Moreover, in cellular and AD models, ThA substantially inhibits ferroptosis by reducing ROS, lipid peroxide generation, and iron accumulation. Furthermore, ThA significantly delays paralysis, ameliorates food-sensing deficits and increases worms' antioxidative capacity. ThA ameliorates AD by inhibiting neuronal ferroptosis mediated by GPX4 activation through its binding with GPX4 and the upregulation of the AMPK/Nrf2/GPX4 pathway.

Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows: (1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group. (2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group. (3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury. (4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group. (5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2 (ACSF2) and iron-responsive element-binding protein 2 (IREB2) were up-regulated in the Deferoxamine group. (6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.

Background: The incidence of gestational diabetes mellitus (GDM) is the first diabetes in pregnancy and has gradually increased worldwide, increasing the burden of social healthcare systems. In GDM, oxidative stress induced by reactive oxygen species (ROS) can disrupt the integrity of the cell membrane through lipid peroxidation reactions and trigger ferroptosis, further exacerbating pancreatic islet β-cell dysfunction and insulin resistance. Lipid peroxidation products related to ferroptosis (such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)), along with the decrease in glutathione peroxidase 4 (GPX4) activity, may be involved in the placental oxidative damage and adverse fetal outcomes in GDM, suggesting that targeting the antioxidant pathway or regulating ferroptosis may serve as an intervention strategy. Legumain (LGMN) can serve as novel targets in diabetes mellitus genetic therapy. Objective: This study investigated the mechanism and effects of LGMN in GDM. Method: All blood samples of normal or patients with GDM were collected by Beijing Ditan Hospital Affiliated Capital Medical University. C57BL/6J female mice were intraperitoneally injected with streptozotocin. Sh-LGMN virus (20 μg of each) or control vector virus (20 μg of each) was injected into GDM mice. GDM mice randomly assigned to three groups (Number = 10). Sh-LGMN virus (20 μg of each) + HSP90 inhibitor or Sh-LGMN virus (20 μg of each) or control vector virus (20 μg of each) was injected into GDM mice. LGMN or si-LGMN Plasmids were transfected into HepG2 cells using Lipofectamine 2000. HepG2 cells were incubated by different insulin concentrations (100 nmol/L) treatment for 24 h. Microarray analysis, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, proliferation assay, ethynyl deoxyuridine staining, bioluminescence imaging, and Western blot were used in this study. Results: Serum LGMN mRNA expression was significantly elevated in patients with GDM. LGMN mRNA and protein expression were also elicited in the liver tissue of GDM mice. LGMN mRNA expression exhibited a positive correlation with Body Mass Index (BMI), fasting plasma glucose, 1-h plasma glucose, or 2-h plasma glucose in patients. Sh-LGMN virus reduced blood glucose levels and body weight, inhibited fasting insulin (FINS) levels and Homeostatic Model Assessment of Beta-cell function (HOMA-β), enhanced Fasting Blood Glucose (FBG)/FINS/Total Cholesterol/Triglycerides levels, improved hepatic fibrosis (HE staining), and also upgraded HbAIc and HOMA-IR in mice of GDM. LGMN exacerbated ROS-induced oxidative stress in the in vitro model of GDM. LGMN promoted ferroptosis in vitro model of GDM. LGMN expanded ROS-induced mitochondrial damage in vitro model of GDM. LGMN inhibited the HSP90/GPX4 Signaling Pathway in the model of GDM. The inhibition of HSP90 reduced LGMN on GDM in the mice model or the in vitro model of GDM. LGMN interlinked with complex protein body of HSP90 and GPX4, which LGMN inhibited the HSP90/GPX4 Signaling Pathway. Conclusions: The LGMN level in patients with GDM was upregulated, and LGMN facilitates ferroptosis by HSP90 and GPX4 in the mice model of GDM and may lead to therapeutic potential of ferroptosis or liver gluconeogenesis in the model of GDM.

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 c − ), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System X c − /GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System X c − /GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System X c − /GSH/GPX4 axis in the treatment of drug-resistant solid tumors.

Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.

Ferroptosis is a type of iron-dependent regulated necrosis induced by lipid peroxidation that occurs in cellular membranes. Among the various lipids, polyunsaturated fatty acids (PUFAs) associated with several phospholipids, such as phosphatidylethanolamine (PE) and phosphatidylcholine (PC), are responsible for ferroptosis-inducing lipid peroxidation. Since the de novo synthesis of PUFAs is strongly restricted in mammals, cells take up essential fatty acids from the blood and lymph to produce a variety of PUFAs via PUFA biosynthesis pathways. Free PUFAs can be incorporated into the cellular membrane by several enzymes, such as ACLS4 and LPCAT3, and undergo lipid peroxidation through enzymatic and non-enzymatic mechanisms. These pathways are tightly regulated by various metabolic and signaling pathways. In this review, we summarize our current knowledge of how various lipid metabolic pathways are associated with lipid peroxidation and ferroptosis. Our review will provide insight into treatment strategies for ferroptosis-related diseases.

Acute liver failure (ALF) is an inflammation‐mediated hepatocyte death process associated with ferroptosis. Avicularin (AL), a Chinese herbal medicine, exerts anti‐inflammatory and antioxidative effects. However, the protective effect of AL and the mechanism on ALF have not been reported. Our in vivo results suggest that AL significantly alleviated lipopolysaccharide (LPS)/D‐galactosamine (D‐GalN)‐induced hepatic pathological injury, liver enzymes, inflammatory cytokines, reactive oxygen species and iron levels and increased the antioxidant enzyme activities (malondialdehyde and glutathione). Our further in vitro experiments demonstrated that AL suppressed inflammatory response in LPS‐stimulated RAW 264.7 cells via blocking the toll‐like receptor 4 (TLR4)/myeloid differentiation protein‐88 (MyD88)/nuclear factor kappa B (NF‐κB) pathway. Moreover, AL attenuated ferroptosis in D‐GalN‐induced HepG2 cells by activating the nuclear factor erythroid 2‐related factor 2 (Nrf2)/heme oxygenase 1 (HO‐1)/glutathione peroxidase 4 (GPX4) pathway. Therefore, AL can alleviate inflammatory response and ferroptosis in LPS/D‐GalN‐induced ALF, and its protective effects are associated with blocking TLR4/MyD88/NF‐κB pathway and activating Nrf2/HO‐1/GPX4 pathway. Moreover, AL is a promising therapeutic option for ALF and should be clinically explored.

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.