OBJECTIVES: Pain sensitization, as a core feature of neuropathic pain (NP), is closely associated with inflammatory imbalance within the central nervous system. To investigate the effects of intrathecal injection of noggin (NOG) on mechanical hypersensitivity, microglial (MG) activation and polarization, and iron metabolism in a spinal nerve ligation (SNL)-induced rat model of NP, and to explore the role of signal transducer and activator of transcription 3 (STAT3) in MG phenotypic transformation. METHODS: Sixty-six Sprague-Dawley (SD) rats were randomly divided into 3 groups: Sham, SNL, and SNL+NOG. Paw withdrawal threshold (PWT) was assessed using von Frey filaments. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to detect spinal cord expression of MG activation marker CD11b, STAT3, phosphorylated STAT3 (p-STAT3), M1 polarization markers [CD86, CD32, interleukin (IL)-1β], tumor necrosis factor-alpha (TNF-α), and CC chemokine receptor 2 (CCR2), M2 markers [CD204, CD163, CX3C chemokine receptor 1 (CX3CR1), IL-10, and arginase-1 (ARG-1)], and iron metabolism-related proteins including ferroportin (FPN, gene: SLC40A1), hepcidin (gene: HAMP), transferrin receptor (gene: TFRC), and divalent metal transporter 1 (DMT-1, gene: SLC11A2). p-STAT3 localization in MGs was visualized via immunofluorescence. In vitro, primary MGs were divided into Control, bone morphogenetic protein-4 (BMP4), and BMP4+Stattic (STAT3 inhibitor) groups to examine the effects of STAT3 inhibition on MG activation, polarization, and iron regulation. RESULTS: In vivo, compared with the Sham group, the SNL and SNL+NOG groups exhibited significantly decreased PWT (P<0.05), elevated spinal CD11b and p-STAT3 protein levels (all P<0.05), increased M1 markers (CD86, CD32, IL-1β, TNF-α, and CCR2) (all P<0.05), and decreased M2 markers (CD204 protein; mRNA of CD204, ARG-1) (all P<0.05). Hepcidin protein and mRNA levels of HAMP, SLC11A2, and TFRC were significantly elevated, while FPN protein and SLC40A1 mRNA were reduced (all P<0.05). Compared to SNL alone, the SNL+NOG group showed increased PWT, decreased CD11b, p-STAT3, and M1 marker expression (except TNF-α), increased M2 marker expression, reduced hepcidin and HAMP levels, and increased FPN and SLC40A1 expression (all P<0.05). In vitro, BMP4 treatment increased CD11b, STAT3, p-STAT3, CD86, and hepcidin levels, while reducing CD204 and FPN (all P<0.05). Inhibition STAT3 with Stattic reversed these changes (all P<0.05). CONCLUSIONS NOG alleviates SNL-induced NP by antagonizing the STAT3 signaling pathway, thereby rebalancing microglial polarization and restoring iron metabolism.
Animals ; Neuralgia/drug therapy* ; Rats, Sprague-Dawley ; Microglia/cytology* ; STAT3 Transcription Factor/metabolism* ; Rats ; Iron/metabolism* ; Male ; Signal Transduction/drug effects* ; Carrier Proteins/therapeutic use* ; Homeostasis/drug effects* ; Spinal Cord/metabolism*

OBJECTIVES: To observe the evolution of intrahepatic macrophage polarization in mice with liver fibrosis induced by iron overload. METHODS: Thirty-two C57BL/6 mice (6-8 weeks) were randomized into control group (n=8) and liver fibrosis model group (n=24) induced by aidly intraperitoneal injection of iron dextran. At the 3rd, 5th, and 7th weeks of modeling, 8 mice in the model group were sacrificed for observing liver fibrosis using Masson, Sirius Red and immunohistochemical staining and detecting serum levels of ALT, AST and the levels of serum iron, ferritin, liver total Fe and ferrous Fe. iNOS⁺/F4/80⁺ cells and CD206⁺/F4/80⁺ cells were detected by double immunofluorescence assay to observe the proportion and distribution of M1 and M2 macrophages. The hepatic expressions of Arg-1, iNOS, IL-6, IL-10, and TNF‑α proteins were detected using Western blotting or ELISA, and the expression of CD206 mRNA was detected using RT-PCR. RESULTS: The mice in the model group showed gradual increase of fibrous tissue hyperplasia in the portal area over time, structural destruction of the hepatic lobules and formation of pseudolobules. With the passage of time during modeling, the rat models showed significantly increased hepatic expressions of α-SMA and COL-1, elevated serum levels of ALT, AST, Fe, ferritin, and increased liver total Fe and ferrous Fe levels. The expressions of M1 polarization markers IL-6, TNF‑α, and iNOS all increased with time and reached their peak levels at the 3rd week; The expressions of M2 polarization markers (IL-10 and Arg-1 proteins and CD206 mRNA) significantly increased in the 3rd week and but decreased in the 5th and 7th weeks. CONCLUSIONS Iron overload promotes M1 polarization of macrophages in mice. Liver fibrosis in the early stage promotes M2 polarization of macrophages but negatively regulate M2 polarization at later stages.
Animals ; Mice ; Mice, Inbred C57BL ; Iron Overload/pathology* ; Macrophages/metabolism* ; Male ; Liver Cirrhosis/etiology* ; Nitric Oxide Synthase Type II/metabolism* ; Interleukin-10/metabolism* ; Liver/pathology* ; Interleukin-6/metabolism* ; Mannose Receptor ; Tumor Necrosis Factor-alpha/metabolism* ; Mannose-Binding Lectins/metabolism* ; Arginase

Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
Ferroptosis/drug effects* ; Humans ; Iron/metabolism* ; Glioblastoma/metabolism* ; Tumor Suppressor Protein p53/metabolism* ; Homeostasis/physiology* ; Ferritins/metabolism* ; Brain Neoplasms/genetics* ; Mutation ; Astrocytes/drug effects* ; Cell Line, Tumor ; Piperazines/pharmacology* ; Quaternary Ammonium Compounds/pharmacology* ; Ferric Compounds

Ferroptosis is a form of cell death elicited by an imbalance in intracellular iron concentrations, leading to enhanced lipid peroxidation. In neurological disorders, both oxidative stress and mitochondrial damage can contribute to ferroptosis, resulting in nerve cell dysfunction and death. The ubiquitin-proteasome system (UPS) refers to a cellular pathway in which specific proteins are tagged with ubiquitin for recognition and degradation by the proteasome. In neurological conditions, the UPS plays a significant role in regulating ferroptosis. In this review, we outline how the UPS regulates iron metabolism, ferroptosis, and their interplay in neurological diseases. In addition, we discuss the future application of small-molecule inhibitors and identify potential drug targets. Further investigation into the mechanisms of UPS-mediated ferroptosis will provide novel insights and strategies for therapeutic interventions and clinical applications in neurological diseases.
Ferroptosis/physiology* ; Humans ; Proteasome Endopeptidase Complex/metabolism* ; Nervous System Diseases/metabolism* ; Animals ; Ubiquitin/metabolism* ; Iron/metabolism*

As a novel form of cell death, ferroptosis is mainly regulated by the accumulation of soluble iron ions in the cytoplasm and the production of lipid peroxides and is closely associated with several diseases, including acute kidney injury, ischemic reperfusion injury, neurodegenerative diseases, and cancer. The term "immunosuppression" refers to various factors that can directly harm immune cells' structure and function and affect the synthesis, release, and biological activity of immune molecules, leading to the insufficient response of the immune system to antigen production, failure to successfully resist the invasion of foreign pathogens, and even organ damage and metabolic disorders. An immunosuppressive phase commonly occurs in the progression of many ferroptosis-related diseases, and ferroptosis can directly inhibit immune cell function. However, the relationship between ferroptosis and immunosuppression has not yet been published due to their complicated interactions in various diseases. Therefore, this review deeply discusses the contribution of ferroptosis to immunosuppression in specific cases. In addition to offering new therapeutic targets for ferroptosis-related diseases, the findings will help clarify the issues on how ferroptosis contributes to immunosuppression.
Ferroptosis/immunology* ; Humans ; Immune Tolerance/immunology* ; Animals ; Immunosuppression Therapy ; Iron/metabolism* ; Neoplasms/immunology*

Ferroptosis is a regulated form of cell death, with its core mechanism being intracellular iron overload-induced lipid peroxidation, leading to cellular dysfunction and mitochondrial structural abnormalities. Ferroptosis is closely related to various diseases including neurodegenerative disorders, tumors, and ischemia-reperfusion organ damage, and has become a potential therapeutic target. Iron is essential for life but can also cause cell death. Despite continuous progress in iron-related biomedical research, many questions remain unanswered. Advances in high-throughput technologies, genomics and proteomics are expected to reveal the cellular iron regulatory mechanism and open up new therapeutic approaches for ferroptosis-related diseases. This article reviews the research progress on iron in terms of its biology, metabolism, regulation, and related diseases, aiming to provide clues and references for developing new ferroptosis-targeted therapeutic strategies and facilitating more in-depth molecular studies from multiple perspectives.
Humans ; Ferroptosis/physiology* ; Iron/metabolism* ; Animals ; Neoplasms/metabolism* ; Neurodegenerative Diseases/metabolism*

Ferroptosis, a regulated cell death process distinct from apoptosis, is characterized by iron dysregulation and reactive oxygen species (ROS) accumulation. After intracerebral hemorrhage (ICH), decreased cerebral blood flow and iron released from erythrocytes trigger lipid peroxidation-particularly of polyunsaturated fatty acids (PUFAs)-through a cascade of reactions in local brain tissues, promoting ferroptosis. Mitochondrial dysfunction and neuroinflammation further elevate ROS, exacerbating lipid peroxidation and accelerating neuronal ferroptosis. Thus, PUFA peroxidation and associated metabolic pathways play a critical role in ICH-related neuronal damage. This review summarizes current understanding of how PUFA peroxidation contributes to ferro-ptosis after ICH, discusses key regulatory mechanisms involving lipid and iron metabolism, and highlights potential therapeutic strategies targeting ferroptosis to improve neurological outcomes.
Ferroptosis/physiology* ; Humans ; Cerebral Hemorrhage/pathology* ; Lipid Peroxidation ; Fatty Acids, Unsaturated/metabolism* ; Reactive Oxygen Species/metabolism* ; Iron/metabolism* ; Animals ; Mitochondria/metabolism*

OBJECTIVE: To detect the expression level of T-complex polypeptide 1 (TCP1) in the bone marrow of newly diagnosed acute myeloid leukemia (AML) patients, and explore its correlation with clinical characteristics and prognosis. METHODS: The bone marrow samples from 80 newly diagnosed AML patients and 30 iron deficiency anemia (IDA) patients were collected, and real time fluorescence quantitative PCR was used to detect the expression level of TCP1 . The clinical data of AML patients were collected, and the correlation of TCP1 expression with clinical characteristics and prognosis of patients were analyzed. The impact of TCP1 on overall survival (OS) of AML patients was identified by using Kaplan-Meier curve analysis. Cox regression analysis was used to identify the factors affecting prognosis of AML patients. RESULTS: Compared with IDA patients, the expression of TCP1 was significantly increased in AML patients (P < 0.01). The high expression group of TCP1 showed a higher proportion of patients with ≥60 years and non-remission after treatment, more accompanied by TET2 mutation and poor prognosis but shorter OS compared to the low expression group (all P < 0.05). The results of multivariate Cox regression analysis showed that age, chromosomal abnormalities, therapeutic efficacy and TCP1 expression were independent risk factors affecting prognosis of AML patients (all P < 0.05). CONCLUSION TCP1 is significantly upregulated in AML patients, and its expression is associated with partial clinical features and poor prognosis. It can serve as a prognostic indicator and potential therapeutic target for AML patients.
Gene Expression Regulation, Leukemic ; Leukemia, Myeloid, Acute/metabolism* ; Humans ; Gene Expression Profiling ; Bone Marrow/metabolism* ; Anemia, Iron-Deficiency/metabolism* ; Polymerase Chain Reaction ; Prognosis ; Kaplan-Meier Estimate ; Proportional Hazards Models ; Multivariate Analysis ; Risk Factors ; Chaperonin Containing TCP-1

As an important trace element, iron is involved in a variety of physiological processes. In recent years, studies have found that the occurrence and development of tumors are closely related to abnormal iron metabolism, and the mode of action is obviously heterogeneous. Tumor cells need more iron to promote their survival and proliferation, but iron overload can also have adverse effects on tumor cells, such as ferroptosis. Ferroptosis is a special regulatory mechanism of cell death, which is different from other regulated cell death pathways. It mainly induces cell death through excessive accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS). Recent studies have found that in the blood system, tumor cells of lymphoma and multiple myeloma (MM) are more sensitive to ferroptosis and affect disease progression through a variety of mechanisms. In this review, the mechanisms of ferroptosis in some subtypes of lymphoma and MM are described in detail, and the correlation between ferroptosis of hematological tumor cells and the occurrence and development of hematological tumors is revealed, aiming to provide new ideas for the treatment of these hematological diseases.
Humans ; Iron/metabolism* ; Ferroptosis ; Multiple Myeloma/metabolism* ; Lymphoma/metabolism* ; Reactive Oxygen Species/metabolism* ; Lymphocytes

From the perspective of competitive endogenous RNA(ceRNA) constructed by metastasy-associated lung adenocarcinoma transcript 1(Malat1) and microRNA 16-5p(miR-16-5p), the improvement mechanism of Tonggu Xiaotong Capsules(TGXTC) on the imbalance and disorder of "cholesterol-iron" metabolism in chondrocytes of osteoarthritis(OA) was explored. In vivo experiments, 60 8-week-old C57BL/6 mice were acclimatized and fed for 1 week and then randomly divided into two groups: blank group(12 mice) and modeling group(48 mice). The animals in modeling group were anesthetized by 5% isoflurane inhalation, which was followed by the construction of OA model. They were then randomly divided into model group, TGXTC group, Malat1 overexpression group, and TGXTC+Malat1 overexpression(TGXTC+Malat1-OE) group, with 12 mice in each group. The structural changes of mouse cartilage tissues were observed by Masson staining after the intervention in each group. RT-PCR was employed to detect the mRNA levels of Malat1 and miR-16-5p in cartilage tissues. Western blot was used to analyze the protein expression of ATP-binding cassette transporter A1(ABCA1), sterol regulatory element-binding protein(SREBP), cytochrome P450 family 7 subfamily B member 1(CYP7B1), CCAAT/enhancer-binding protein homologous protein(CHOP), acyl-CoA synthetase long-chain family member 4(ACSL4), and glutathione peroxidase 4(GPX4) in cartilage tissues. In vitro experiments, mouse chondrocytes were induced by thapsigargin(TG), and the combination of Malat1 and miR-16-5p was detected by double luciferase assay. The fluorescence intensity of Malat1 in chondrocytes was determined by fluorescence in situ hybridization. The miR-16-5p inhibitory chondrocyte model was constructed. RT-PCR was used to analyze the levels of Malat1 and miR-16-5p in chondrocytes under the inhibition of miR-16-5p. Western blot was adopted to analyze the regulation of TG-induced chondrocyte proteins ABCA1, SREBP, CYP7B1, CHOP, ACSL4, and GPX4 by TGXTC under the inhibition of miR-16-5p. The results of in vivo experiments showed that,(1) compared with model group, TGXTC group exhibited a relatively complete cartilage layer structure. Compared with Malat1-OE group, TGXTC+Malat1-OE group showed alleviated cartilage surface damage.(2) Compared with model group, TGXTC group had a significantly decreased Malat1 mRNA level and an increased miR-16-5p mRNA level in mouse cartilage tissues(P<0.01).(3) Compared with the model group, the protein levels of ABCA1 and GPX4 in the cartilage tissue of mice in the TGXTC group increased, while the protein levels of SREBP, CYP7B1, CHOP and ACSL4 decreased(P<0.01). The results of in vitro experiments show that,(1) dual-luciferase was used to evaluate that miR-16-5p has a targeting effect on the Malat1 gene.(2)Compared with TG+miR-16-5p inhibition group, TG+miR-16-5p inhibition+TGXTC group had an increased mRNA level of miR-16-5p and an decreased mRNA level of Malat1(P<0.01).(3) Compared with TG+miR-16-5p inhibition group, TG+miR-16-5p inhibition+TGXTC group exhibited increased expression of ABCA1 and GPX4 proteins and decreased expression of SREBP, CYP7B1, CHOP, and ACSL4 proteins(P<0.01). The reasults showed that TGXTC can regulate the ceRNA of Malat1 and miR-16-5p to alleviate the "cholesterol-iron" metabolism disorder of osteoarthritis chondrocytes.
Animals ; MicroRNAs/metabolism* ; RNA, Long Noncoding/metabolism* ; Chondrocytes/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Mice, Inbred C57BL ; Mice ; Osteoarthritis/drug therapy* ; Iron/metabolism* ; Male ; Cholesterol/metabolism* ; Humans ; Capsules ; RNA, Competitive Endogenous