BACKGROUND: Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has been inconsistent across previous studies. We aimed to assess the difference patterns of iron deposition detected by quantitative iron-sensitive magnetic resonance imaging (MRI) between patients with PD and patients with atypical parkinsonian syndromes (APSs), and between patients with PD and healthy controls (HCs). METHODS: A systematic literature search was conducted on PubMed, Embase, and Web of Science databases to identify studies investigating the iron content in PD patients using the iron-sensitive MRI techniques (R2 * and quantitative susceptibility mapping [QSM]), up until May 1, 2023. The quality assessment of case-control and cohort studies was performed using the Newcastle-Ottawa Scale, whereas diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Standardized mean differences and summary estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for iron content, using a random effects model. We also conducted the subgroup-analysis based on the MRI sequence and meta-regression. RESULTS: Seventy-seven studies with 3192 PD, 209 multiple system atrophy (MSA), 174 progressive supranuclear palsy (PSP), and 2447 HCs were included. Elevated iron content in substantia nigra (SN) pars reticulata ( P <0.001) and compacta ( P <0.001), SN ( P <0.001), red nucleus (RN, P <0.001), globus pallidus ( P <0.001), putamen (PUT, P = 0.021), and thalamus ( P = 0.029) were found in PD patients compared with HCs. PD patients showed lower iron content in PUT ( P <0.001), RN ( P = 0.003), SN ( P = 0.017), and caudate nucleus ( P = 0.017) than MSA patients, and lower iron content in RN ( P = 0.001), PUT ( P <0.001), globus pallidus ( P = 0.004), SN ( P = 0.015), and caudate nucleus ( P = 0.001) than PSP patients. The highest diagnostic accuracy distinguishing PD from HCs was observed in SN (AUC: 0.85), and that distinguishing PD from MSA was found in PUT (AUC: 0.90). In addition, the best diagnostic performance was achieved in the RN for distinguishing PD from PSP (AUC: 0.86). CONCLUSIONS: Quantitative iron-sensitive MRI could quantitatively detect the iron content of subcortical nuclei in PD and APSs, while it may be insufficient to accurately diagnose PD. Future studies are needed to explore the role of multimodal MRI in the diagnosis of PD. REGISTRISION PROSPERO (CRD42022344413).
Humans ; Parkinson Disease/diagnostic imaging* ; Magnetic Resonance Imaging/methods* ; Iron/metabolism*

Ferroptosis, an iron-dependent programmed cell death process driven by reactive oxygen species-mediated lipid peroxidation, is regulated by several metabolic processes, including iron metabolism, lipid metabolism, and redox system. Macrophages are a group of innate immune cells that are widely distributed throughout the body, and play pivotal roles in maintaining metabolic balance by its phagocytic and efferocytotic effects. There is a profound association between the biological functions of macrophage and ferroptosis. Therefore, this review aims to elucidate three key aspects of the unique relationship between macrophages and ferroptosis, including macrophage metabolism and their regulation of cellular ferroptosis; ferroptotic stress that modulates functions of macrophage and promotion of inflammation; and the effects of macrophage ferroptosis and its role in diseases. Finally, we also summarize the possible mechanisms of macrophages in regulating the ferroptosis process at the global and local levels, as well as the role of ferroptosis in the macrophage-mediated inflammatory process, to provide new therapeutic insights for a variety of diseases.
Ferroptosis/physiology* ; Macrophages/metabolism* ; Humans ; Animals ; Iron/metabolism* ; Reactive Oxygen Species/metabolism* ; Lipid Peroxidation/physiology* ; Inflammation/metabolism*

Cardiovascular disease remains the leading cause of death in China, with its morbidity and mortality continue to rise. Ferroptosis, a unique form of iron-dependent cell death, plays a major role in many heart diseases. The classical mechanisms of ferroptosis include iron metabolism disorder, oxidative antioxidant imbalance and lipid peroxidation. Recent studies have found many additional mechanisms of ferroptosis, such as coenzyme Q10, ferritinophagy, lipid autophagy, mitochondrial metabolism disorder, and the regulation by nuclear factor erythroid 2-related factor 2 (NRF2). This article reviews recent advances in understanding the mechanisms of ferroptosis and its role in heart failure, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, myocardial toxicity of doxorubicin, septic cardiomyopathy, and arrhythmia. Furthermore, we discuss the potential of ferroptosis inhibitors/inducers as therapeutic targets for heart diseases, suggesting that ferroptosis may be an important intervention target of heart diseases.
Ferroptosis/physiology* ; Humans ; Heart Diseases/physiopathology* ; NF-E2-Related Factor 2/physiology* ; Animals ; Myocardial Reperfusion Injury/physiopathology* ; Lipid Peroxidation ; Heart Failure/physiopathology* ; Iron/metabolism* ; Diabetic Cardiomyopathies/physiopathology* ; Ubiquinone/analogs & derivatives*

Nuclear receptor co-activator 4 (NCOA4) acts as a selective cargo receptor that binds to ferritin, a cytoplasmic iron storage complex. By mediating ferritinophagy, NCOA4 regulates iron metabolism and releases free iron in the body, thus playing a crucial role in a variety of biological processes, including growth, development, and metabolism. Recent studies have shown that NCOA4-mediated ferritinophagy is closely associated with the occurrence and development of iron metabolism-related diseases, such as liver fibrosis, renal cell carcinoma, and neurodegenerative diseases. In addition, a number of clinical drugs have been identified to modulate NCOA4-mediated ferritinophagy, significantly affecting disease progression and treatment efficacy. This paper aims to review the current research progress on the role of NCOA4-mediated ferritinophagy in related diseases, in order to provide new ideas for targeted clinical therapy.
Humans ; Nuclear Receptor Coactivators/physiology* ; Ferritins/metabolism* ; Animals ; Neurodegenerative Diseases/metabolism* ; Iron/metabolism* ; Autophagy/physiology* ; Liver Cirrhosis/metabolism* ; Carcinoma, Renal Cell/metabolism* ; Kidney Neoplasms/physiopathology*

Recent studies have shown that an imbalance in iron metabolism can affect the composition and microstructural changes of bone, disrupting bone homeostasis and leading to osteoporosis(OP). The imbalance in iron metabolism, along with its induced local abnormal microenvironment and cellular iron death, has become a new focal point in OP research, drawing increasing attention from the academic community regarding the regulation of iron metabolism to prevent and manage OP. From the perspective of traditional Chinese medicine(TCM), iron metabolism imbalance has potential connections to TCM theories regarding internal organs, as well as treatments aimed at tonifying the kidney, strengthening the spleen, and activating blood circulation. Evidence is continually emerging that TCMs and effective components that tonify the kidney, strengthen the spleen, and activate blood circulation can prevent and manage OP by regulating iron metabolism. This article analyzes the relationship between iron and bone, as well as the effects of TCM formulations on improving iron metabolism and influencing bone metabolism, from the perspectives of iron metabolism mechanisms and TCM interventions, aiming to broaden existing clinical strategies for prevention and treatment and inject new momentum into the field of OP as it moves into a new era.
Osteoporosis/drug therapy* ; Humans ; Iron/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Animals ; Medicine, Chinese Traditional ; Bone and Bones/drug effects*

Haematitum and Limonitum are two iron-containing mineral medicines included in the 2020 edition of the Chinese Pharmacopoeia. They have similar main components and major differences in their property, flavor, channel tropism, and clinical uses. In this study, we investigated the surface properties, mineral composition, mineral dissociation, elemental composition, and iron state of Haematitum and Limonitum to explore their mineralogical differences. Scanning electron microscopy(SEM), specific surface and porosity analyzer, X-ray diffractometer(XRD), X-ray photoelectron spectrometer(XPS), and advanced mineral identification and characterization system(AMICS) were used to analyze the mineralogy of Haematitum and Limonitum. The results showed that Haematitum had an angular surface with granular attachments and a specific surface area of 17.04 m~2·g~(-1). In comparison, Limonitum had a smooth and flat surface with a bundled acicular crystal structure and a specific surface area of 46.29 m~2·g~(-1). Haematitum consists of 31 detectable minerals containing 18 elements, with the major element, iron(44.5% Fe~(2+) and 55.5% Fe~(3+)) distributed in 17 minerals, including hematite, iron oxide, knebelite, siderite, and magnesioferrite. Limonitum consists of 32 detectable minerals containing 17 elements, with the major element, iron(14.5% Fe~(2+) and 85.5% Fe~(3+)) distributed in 19 minerals, including limonite, iron oxide, chlorite, and knebelite. In summary, the elemental composition of Haematitum and Limonitum does not differ greatly, but there are large differences in the mineral composition and iron state. The large specific surface area and strong adsorption capacity of Limonitum may be one of the mechanisms of its anti-diarrheal action. The Fe_2O_3 and illite contained in Haematitum and Limonitum may be the key substances for their hemostasis effects. The mineralogical differences are expected to provide a reference for explaining the scientific connotation of mineral medicine and laying a material foundation for studying its mechanism of action.
Iron/analysis* ; Minerals/chemistry* ; Drugs, Chinese Herbal/chemistry* ; X-Ray Diffraction ; Microscopy, Electron, Scanning ; Photoelectron Spectroscopy

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

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*

Iron overload is a major complication of thalassemia, clinically manifested as heart failure, liver cirrhosis, diabetes, growth and development retardation, and delayed sexual development, with severe cases leading to death. Standardized iron chelation therapy is essential to ensure long-term and high-quality survival for patients. This guideline provides recommendations on methods for detecting iron overload, the timing for initiating iron chelation therapy, treatment strategies for transfusion-dependent and non-transfusion-dependent thalassemia, and special circumstances regarding iron chelation therapy, serving as a reference for iron chelation treatment in thalassemia.
Humans ; Thalassemia/drug therapy* ; Iron Chelating Agents/therapeutic use* ; Iron Overload/diagnosis* ; Chelation Therapy

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*