Paracoccidioidomycosis (PCM) is caused by Paracoccidioides spp.; during infection, some host mechanisms limit the availability of iron, thereby reducing its reproduction. However, Paracoccidioides spp. can evade the immune defense and, even under limited iron conditions, use this mineral for growth and dissemination. This study evaluated the iron metabolism of 39 patients who were diagnosed with chronic PCM from 2013 to 2021. The forms of iron before treatment and at the time of clinical cure were evaluated based on the following: serum ferritin levels (storage iron); total iron-binding capacity (TIBC) and transferrin saturation (TSAT) level (transport iron); red blood cell (RBC), hemoglobin (Hb), hematocrit (HCT), and soluble transferrin receptor (sTfR) levels; and sTfR/log ferritin ratio (functional iron). The mean age of the patients was 54.5 years (±6.7 years). Most patients were men (97.4%), rural workers (92.1%), and smokers (84.6%); furthermore, most had moderate disease severity (66.7%). After achieving clinical cure, we observed that serum ferritin levels decreased, and parameters of functional iron increased. The extent of alteration in these parameters were more pronounced in severe cases than in to mild or moderate cases. Furthermore, moderate correlations were observed between C-reactive protein and the Hb (r = -0.500; p = 0.002), RBC (r = -0.461; p = 0.005), HCT (r = -0.514; p = 0.001), and iron levels (r = -0.491; p = 0.002). However, it is possible to infer that PCM interferes with functional and storage iron because improvements in these parameters after treatment as well as associations with disease severity were observed. PCM can lead to anemia of inflammation, which can be differentiated from iron deficiency anemia by a careful investigation of the iron form parameters.

Copper (Cu) and Iron (Fe) has been the subject of intensive research over several decades as numerous seminal studies robustly support the involvement of Cu and Fe metabolism dyshomeostasis as a common denominator in several neurodegenerative disorders (particularly Alzheimer's disease and Parkinson's disease); however, till date, the exact "cause-effect" association has not been elucidated. Thus, there is urgent need to look for newer association/pathways of these redox active elements in different neuropathological conditions. Therefore, in this study, we have used bioinformatics based approach to identify novel Cu and Fe metabolism proteins in neurodegenerative disorders using Cytoscape software. The network biology data demonstrated the association of secreted protein acidic and rich in cysteine (SPARC/osteonectin) protein with Alzheimer's disease, Parkinson's disease, Huntington's disease and neurodegeneration with brain iron accumulation (NBIA) disease, whereas Coagulation factor V may have a role in Brunner Syndrome, Obsessive-Compulsive Disorder, Febrile seizures and Schizophrenia diseases. Further analysis revealed Coagulation factor VII possible role in L1 Syndrome and Congenital hydrocephalus disorders. In conclusion, the present study shows the first evidence in silico that SPARC/osteonectin, Coagulation factor V and VII proteins may have plausible role in the pathogenesis of various neurodegenerative diseases.

Every cell of the mammalian organism needs iron as trace element in numerous oxido-reductive processes as well as for transport and storage of oxygen. The very versatility of ionic iron makes it a toxic entity which can catalyze the production of radicals that damage vital membranous and macromolecular assemblies in the cell. The mammalian organism maintains therefore a complex regulatory network of iron uptake, excretion and intra-body distribution. Intracellular regulation in different cell types is intertwined with a global hormonal signalling structure. Iron deficiency as well as excess of iron are frequent and serious human disorders. They can affect every cell, but also the organism as a whole.

A wealth of human and experimental studies document a causal and aggravating role of iron deficiency in neurodevelopmental disorders. While pre-, peri-, and early postnatal iron deficiency sets the stage for the risk of developing neurodevelopmental disorders, iron deficiency acquired at later ages aggravates pre-existing neurodevelopmental disorders. Yet, the association of iron deficiency and neurodevelopmental disorders in childhood and adolescence has not yet been explored comprehensively. In this scoping review, we investigate 1) the association of iron deficiency in children and adolescents with the most frequent neurodevelopmental disorders, ADHD, ASD, and FASD, and 2) whether iron supplementation improves outcomes in these disorders.

Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system.

Ferroptosis is implicated in a range of brain disorders, but it is unknown whether neurons or glia in the brain are particularly effected. Here, we report that primary cortical astrocytes (PA), microglia (PM), and neurons (PN) varied in their sensitivities to ferroptosis. Specifically, PM were the most sensitive to ferroptosis, while PN were relatively insensitive. In contrast, PN and PM were equally susceptible to apoptosis, with PA being less affected, whereas all three cell types were similarly susceptible to autophagic cell death. In the tri-culture system containing PA, PM, and PN, the cells were more resistant to ferroptosis than that in the monoculture. These results demonstrated that brain cells exhibit different sensitivities under ferroptosis stress and the difference may be explained by the differentially regulated iron metabolism and the ability to handle iron. Continued elucidation of the cell death patterns of neurons and glia will provide a theoretical basis for related strategies to inhibit the death of brain cells.

Iron is required for most forms of organisms, and it is the most essential element for the functions of many iron-containing proteins involved in oxygen transport, cellular respiration, DNA replication, and so on. Disorders of iron metabolism are associated with diverse diseases, including anemias (e.g., iron-deficiency anemia and anemia of chronic diseases) and iron overload diseases, such as hereditary hemochromatosis and β-thalassemia. Hepcidin (encoded by Hamp gene) is a peptide hormone synthesized by hepatocytes, and it plays an important role in regulating the systematic iron homeostasis. As the systemic iron regulator, hepcidin, not only controls dietary iron absorption and iron egress out of iron storage cells, but also induces iron redistribution in various organs. Deregulated hepcidin is often seen in a variety of iron-related diseases including anemias and iron overload disorders. In the case of iron overload disorders (e.g., hereditary hemochromatosis and β-thalassemia), hepatic hepcidin concentration is significantly reduced.Since hepcidin deregulation is responsible for iron disorder-associated diseases, the purpose of this review is to summarize the recent findings on therapeutics targeting hepcidin.Continuous efforts have been made to search for hepcidin mimics and chemical compounds that could be used to increase hepcidin level. Here, a literature search was conducted in PubMed, and research papers relevant to hepcidin regulation or hepcidin-centered therapeutic work were reviewed. On the basis of literature search, we recapitulated recent findings on therapeutic studies targeting hepcidin, including agonists and antagonists to modulate hepcidin expression or its downstream signaling. We also discussed the molecular mechanisms by which hepcidin level and iron metabolism are modulated.Elevating hepcidin concentration is an optimal strategy to ameliorate iron overload diseases, and also to relieve β-thalassemia phenotypes by improving ineffective erythropoiesis. Relative to the current conventional therapies, such as phlebotomy and blood transfusion, therapeutics targeting hepcidin would open a new avenue for treatment of iron-related diseases.

Vitamin D is a prohormone nutrient, which is involved in skeletal and extra-skeletal functions. Iron is another essential nutrient that is necessary for the production of red blood cells and oxygen transport. This element plays important roles in enzymatic systems including those required for Vitamin D activation. To the best of our knowledge, there is no exclusive review on the relationship between iron deficiency anemia (IDA), as the most prevalent type of anemia, and Vitamin D deficiency and the effect of recovery from iron deficiency on Vitamin D status. The aim of this study was to conduct a systematic search of observational and clinical trials in this field. The databases of PubMed, ProQuest, Cochrane Library, ISI Web of Knowledge, and SCOPUS were searched comprehensively. English-language human studies conducted on iron deficient patients or interventions on the effect of iron therapy on Vitamin D were extracted (n = 10). Our initial search yielded 938 articles. A total of 23 papers met the inclusion criteria. Thirteen studies were excluded because they were not relevant or not defining anemia types. The final analysis was performed on ten articles (3 cross-sectional and 7 interventional studies). Observational data indicated a positive relationship between iron status and Vitamin D, while trials did not support the effectiveness of iron supplementation on improving Vitamin D status. The mechanism underlying this association may involve the reduction of the activation of hydroxylases that yield calcitriol. Future randomized controlled trials with large sample sizes and proper designs are needed to highlight underlying mechanisms.

The immunosuppressive regulatory T (Treg) cells exert emerging effects on adipose tissue homeostasis and systemic metabolism. However, the metabolic regulation and effector mechanisms of Treg cells in coping with obesogenic insults are not fully understood. We have previously established an indispensable role of the O-linked N-Acetylglucosamine (O-GlcNAc) signaling in maintaining Treg cell identity and promoting Treg suppressor function, via STAT5 O-GlcNAcylation and activation. Here, we investigate the O-GlcNAc transferase (OGT)-STAT5 axis in driving the immunomodulatory function of Treg cells for metabolic homeostasis. Treg cell-specific OGT deficiency renders mice more vulnerable to high-fat diet (HFD)-induced adiposity and insulin resistance. Conversely, constitutive STAT5 activation in Treg cells confers protection against adipose tissue expansion and impaired glucose and insulin metabolism upon HFD feeding, in part by suppressing adipose lipid uptake and redistributing systemic iron storage. Treg cell function can be augmented by targeting the OGT-STAT5 axis to combat obesity and related metabolic disorders.

A growing set of observations points to mitochondrial dysfunction, iron accumulation, oxidative damage and chronic inflammation as common pathognomonic signs of a number of neurodegenerative diseases that includes Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, Friedrich's ataxia and Parkinson's disease. Particularly relevant for neurodegenerative processes is the relationship between mitochondria and iron. The mitochondrion upholds the synthesis of iron-sulfur clusters and heme, the most abundant iron-containing prosthetic groups in a large variety of proteins, so a fraction of incoming iron must go through this organelle before reaching its final destination. In turn, the mitochondrial respiratory chain is the source of reactive oxygen species (ROS) derived from leaks in the electron transport chain. The co-existence of both iron and ROS in the secluded space of the mitochondrion makes this organelle particularly prone to hydroxyl radical-mediated damage. In addition, a connection between the loss of iron homeostasis and inflammation is starting to emerge; thus, inflammatory cytokines like TNF-alpha and IL-6 induce the synthesis of the divalent metal transporter 1 and promote iron accumulation in neurons and microglia. Here, we review the recent literature on mitochondrial iron homeostasis and the role of inflammation on mitochondria dysfunction and iron accumulation on the neurodegenerative process that lead to cell death in Parkinson's disease. We also put forward the hypothesis that mitochondrial dysfunction, iron accumulation and inflammation are part of a synergistic self-feeding cycle that ends in apoptotic cell death, once the antioxidant cellular defense systems are finally overwhelmed.

The current treatments applied in aquaculture to limit disease dissemination are mostly based on the use of antibiotics, either as prophylactic or therapeutic agents, with vaccines being available for a limited number of fish species and pathogens. Antimicrobial peptides are considered as promising novel substances to be used in aquaculture, due to their antimicrobial and immunomodulatory activities. Hepcidin, the major iron metabolism regulator, is found as a single gene in most mammals, but in certain fish species, including the European sea bass (Dicentrarchus labrax), two different hepcidin types are found, with specialized roles: the single type 1 hepcidin is involved in iron homeostasis trough the regulation of ferroportin, the only known iron exporter; and the various type 2 hepcidins present antimicrobial activity against a number of different pathogens. In this study, we tested the administration of sea bass derived hepcidins in models of infection and iron overload. Administration with hamp2 substantially reduced fish mortalities and bacterial loads, presenting itself as a viable alternative to the use of antibiotics. On the other hand, hamp1 seems to attenuate the effects of iron overload. Further studies are necessary to test the potential protective effects of hamp2 against other pathogens, as well as to understand how hamp2 stimulate the inflammatory responses, leading to an increased fish survival upon infection.

Background: Because the pathogenesis of high altitude polycythemia (HAPC) is unclear, the aim of the present study was to explore whether abnormal iron metabolism is involved in the pathogenesis of HAPC and the possible cause. Methods: We examined the serum levels of iron, total iron binding capacity, soluble transferrin receptor (sTfR), ferritin, and hepcidin as well as erythropoietin (EPO) and inflammation-related cytokines in 20 healthy volunteers at sea level, 36 healthy high-altitude migrants, and 33 patients with HAPC. Mice that were exposed to a simulated hypoxic environment at an altitude of 5,000 m for 4 weeks received exogenous iron or intervention on cytokines, and the iron-related and hematological indices of peripheral blood and bone marrow were detected. The in vitro effects of some cytokines on hematopoietic cells were also observed. Results: Iron mobilization and utilization were enhanced in people who had lived at high altitudes for a long time. Notably, both the iron storage in ferritin and the available iron in the blood were elevated in patients with HAPC compared with the healthy high-altitude migrants. The correlation analysis indicated that the decreased hepcidin may have contributed to enhanced iron availability in HAPC, and decreased interleukin (IL)-10 and IL-22 were significantly associated with decreased hepcidin. The results of the animal experiments confirmed that a certain degree of iron redundancy may promote bone marrow erythropoiesis and peripheral red blood cell production in hypoxic mice and that decreased IL-10 and IL-22 stimulated iron mobilization during hypoxia by affecting hepcidin expression. Conclusion: These data demonstrated, for the first time, that an excess of obtainable iron caused by disordered IL-10 and IL-22 was involved in the pathogenesis of some HAPC patients. The potential benefits of iron removal and immunoregulation for the prevention and treatment of HAPC deserve further research.

Iron withholding, an essential component of nutritional immunity, plays a fundamental role in host resistance to Salmonella infection. Our previous study showed that SpvB, an important pSLT-encoded cytotoxic effector, facilitated Salmonella pathogenesis within macrophages via perturbing cellular iron metabolism. However, the underlying mechanisms of SpvB in Salmonella-relevant disorders of systemic iron metabolism have not yet been identified. Here, we demonstrated that SpvB facilitated Salmonella to scavenge iron from the host by modulating the hepcidin-ferroportin axis, a key regulator of systemic iron metabolism. We observed that SpvB enhanced hepatic hepcidin synthesis in a STAT3-dependent manner, but not the BMP/SMAD pathway. This subsequently resulted in a reduction of the unique cellular iron exporter ferroportin, which facilitated hypoferremia and hepatic iron accumulation and ultimately countered the limitation of iron availability, thereby improving the chances of Salmonella survival and replication. Moreover, SpvB promoted the production of proinflammatory molecules associated with the infiltration of inflammatory cells via highly upregulating TREM-1 signaling. Our data supported a role of TREM-1 in SpvB-related dysregulation of host iron metabolism and suggested that targeting TREM-1 might provide a potential therapeutic strategy to prevent or alleviate Salmonella pathogenesis.

The ubiquitous mold Scedosporium apiospermum is increasingly recognized as an emerging pathogen, especially among patients with underlying disorders such as immunodeficiency or cystic fibrosis (CF). Indeed, it ranks the second among the filamentous fungi colonizing the respiratory tract of CF patients. However, our knowledge about virulence factors of this fungus is still limited. The role of iron-uptake systems may be critical for establishment of Scedosporium infections, notably in the iron-rich environment of the CF lung. Two main strategies are employed by fungi to efficiently acquire iron from their host or from their ecological niche: siderophore production and reductive iron assimilation (RIA) systems. The aim of this study was to assess the existence of orthologous genes involved in iron metabolism in the recently sequenced genome of S. apiospermum. At first, a tBLASTn analysis using A. fumigatus iron-related proteins as query revealed orthologs of almost all relevant loci in the S. apiospermum genome. Whereas the genes putatively involved in RIA were randomly distributed, siderophore biosynthesis and transport genes were organized in two clusters, each containing a non-ribosomal peptide synthetase (NRPS) whose orthologs in A. fumigatus have been described to catalyze hydroxamate siderophore synthesis. Nevertheless, comparative genomic analysis of siderophore-related clusters showed greater similarity between S. apiospermum and phylogenetically close molds than with Aspergillus species. The expression level of these genes was then evaluated by exposing conidia to iron starvation and iron excess. The expression of several orthologs of A. fumigatus genes involved in siderophore-based iron uptake or RIA was significantly induced during iron starvation, and conversely repressed in iron excess conditions. Altogether, these results indicate that S. apiospermum possesses the genetic information required for efficient and competitive iron uptake. They also suggest an important role of the siderophore production system in iron uptake by S. apiospermum.

Vitamin C (Vit C) and iron metabolism are closely related to metabolic disorders. However, the relation between iron storage protein ferritin and Vit C has not been elucidated. We aimed to investigate the crosstalk between Vit C and ferritin and its implications on non-alcoholic fatty liver disease (NAFLD). Clinical information of 3,614 subjects was obtained from the NHANES Public Data 2017-2018. FibroScan data, which estimates liver steatosis and fibrosis and Vit C, were selected to assess factors influencing NAFLD in this cross-sectional study. Ferritin and Vit C among different categories of liver steatosis and fibrosis were assessed by CAP and E value. Logistic regression and RCS models were used to analyze the correlations. In vitro study in hepG2 were conducted to validate the regulations. Ferritin increased while Vit C decreased with more severe hepatic steatosis and hepatic fibrosis (all P < 0.001). Logistic regression models indicated that increased serum ferritin was a risk factor for NAFLD while increased Vit C was a protective factor for NAFLD and hepatic fibrosis after adjusting the continuous and categorical variables. Vitamin C was negatively associated with ferritin. Further mediation analysis identified that ferritin mediates the impact of Vit C on NAFLD (P < 0.05) and cirrhosis (P < 0.001). The experiments on cellular level suggested Vit C alleviated PA/OA induced steatosis and maintains iron homeostasis through inhibiting PA/OA induced upregulation of iron bound protein ferritin and labile iron pool (LIP) induction in hepG2 cells. In conclusion, Vit C was a protective factor, whereas ferritin was a risk factor for hepatic steatosis and fibrosis. Vitamin C alleviated NAFLD and maintained iron homeostasis via ferritin suppression and LIP induction.

Progressive iron accumulation in the brain and iron-induced oxidative stress are considered to be one of the initial causes of Alzheimer's disease (AD), and modulation of brain iron level shows promise for its treatment. Hepcidin expressed by astrocytes has been speculated to regulate iron transport across the blood-brain barrier (BBB) and control the whole brain iron load. Whether increasing the expression of astrocyte hepcidin can reduce brain iron level and relieve AD symptoms has yet to be studied. Here, we overexpressed hepcidin in astrocytes of the mouse brain and challenged the mice with amyloid-β25-35 (Aβ25-35) by intracerebroventricular injection. Our results revealed that hepcidin overexpression in astrocytes significantly ameliorated Aβ25-35-induced cell damage in both the cerebral cortex and hippocampus. This protective role was also attested by behavioral tests of the mice. Our data further demonstrated that astrocyte-overexpressed hepcidin could decrease brain iron level, possibly by acting on ferroportin 1 (FPN1) on the brain microvascular endothelial cells (BMVECs), which in turn reduced Aβ25-35-induced oxidative stress and apoptosis, and ultimately protected cells from damage. This study provided in vivo evidences of the important role of astrocyte hepcidin in the regulation of brain iron metabolism and protection against Aβ-induced cortical and hippocampal damages and implied its potential in the treatment of oxidative stress-related brain disorders.

Multiple sclerosis (MS) is a chronic inflammatory disease of autoimmune origin for which there is currently no available cure. In the course of MS, next to neurological disorders, patients often present with chronic fatigue syndrome and depressive disorders, which impact on their daily function and quality of life. The aim of study was to analyse the relationship between serum parameters of iron metabolism and the severity of fatigue, depressive symptoms, and quality of life in MS patients.

Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that these behavioral changes could be associated with altered dopaminergic neurotransmission, providing a therapeutic basis for psychiatric disorders caused by Pb toxicity.

Iron deficiency have been found to be linked to sleep disorders. Both genetic and environmental factors are risk factors for skewed iron metabolism, thus sleep disruptions in autism spectrum disorders (ASD). The aim of our study was to assess the prevalence of single nucleotide polymorphisms (SNPs) within transferrin gene (TF) rs1049296 C>T, rs3811647 G>A, transferrin receptor gene (TFR) rs7385804 A>C, and hepcidin antimicrobial peptide gene (HAMP) rs10421768 A>G in Polish individuals with ASD and their impact on sleep pattern. There were 61 Caucasian participants with ASD and 57 non-ASD controls enrolled. Genotypes were determined by real-time PCR using TaqMan SNP assays. The Athens Insomnia Scale (AIS) was used to identify sleep disruptions. There were 32 cases (57.14%) with insomnia identified. In the ASD group, the defined counts of genotypes were as follows: TF rs1049296, C/C n = 41 and C/T n = 20; TF rs3811647, G/G n = 22, G/A n = 34, and A/A n = 5; TFR rs7385804, A/A n = 22, A/C n = 29, and C/C n = 10; and HAMP rs10421768, A/A n = 34, A/G n = 23, and G/G n = 4. There were no homozygous carriers of the TF rs1049296 C>T minor allele in the ASD group. All analyzed SNPs were not found to be linked to insomnia. The investigated polymorphisms are not predictors of sleep disorders in the analyzed cohort of individuals with ASD.

Brain iron accumulation constitutes a pathognomonic indicator in several neurodegenerative disorders. Metal accumulation associated with dopaminergic neuronal death has been documented in Parkinson's disease. Through the use of in vivo and in vitro models, we demonstrated that lipid dysregulation manifests as a neuronal and glial response during iron overload. In this study, we show that cholesterol content and triacylglycerol (TAG) hydrolysis were strongly elevated in mice midbrain. Lipid cacostasis was concomitant with the loss of dopaminergic neurons, astrogliosis and elevated expression of α-synuclein. Exacerbated lipid peroxidation and markers of ferroptosis were evident in the midbrain from mice challenged with iron overload. An imbalance in the activity of lipolytic and acylation enzymes was identified, favoring neutral lipid hydrolysis, and consequently reducing TAG and cholesteryl ester levels. Notably, these observed alterations were accompanied by motor impairment in iron-treated mice. In addition, neuronal and glial cultures along with their secretomes were used to gain further insight into the mechanism underlying TAG hydrolysis and cholesterol accumulation as cellular responses to iron accumulation. We demonstrated that TAG hydrolysis in neurons is triggered by astrocyte secretomes. Moreover, we found that the ferroptosis inhibitor, ferrostatin-1, effectively prevents cholesterol accumulation both in neurons and astrocytes. Taken together, these results indicate that lipid disturbances occur in iron-overloaded mice as a consequence of iron-induced oxidative stress and depend on neuron-glia crosstalk. Our findings suggest that developing therapies aimed at restoring lipid homeostasis may lead to specific treatment for neurodegeneration associated with ferroptosis and brain iron accumulation.