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Iron oxide nanoparticles (IONPs) have wide applications in the biomedical field due to their outstanding physical and chemical properties. However, the potential adverse effects and related mechanisms of IONPs in human organs, especially the lung, are still largely ignored. In this study, we found that group-modified IONPs (carboxylated, aminated and silica coated) induce slight lung cell damage (in terms of the cell cycle, reactive oxygen species (ROS) production, cell membrane integrity and DNA damage) at a sublethal dosage. However, aminated IONPs could release more iron ions in the lysosome than the other two types of IONPs, but the abnormally elevated iron ion concentration did not induce ferroptosis. Intriguingly, amino-modified IONPs aggravated the accumulation of intracellular peroxides induced by the ferroptosis activator RSL3 and thus caused ferroptosis in vitro, and the coadministration of amino-modified IONPs and RSL3 induced more severe lung injury in vivo. Therefore, our data revealed that the surface functionalization of IONPs plays an important role in determining their potential pulmonary toxicity, as surface modification influences their degradation behavior. These results provide guidance for the design of future IONPs and the corresponding safety evaluations and predictions.

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Stem cell niche is critical for regulating the behavior of stem cells. Drosophila neural stem cells (Neuroblasts, NBs) are encased by glial niche cells closely, but it still remains unclear whether glial niche cells can regulate the self-renewal and differentiation of NBs. Here, we show that ferritin produced by glia, cooperates with Zip13 to transport iron into NBs for the energy production, which is essential to the self-renewal and proliferation of NBs. The knockdown of glial ferritin encoding genes causes energy shortage in NBs via downregulating aconitase activity and NAD+ level, which leads to the low proliferation and premature differentiation of NBs mediated by Prospero entering nuclei. More importantly, ferritin is a potential target for tumor suppression. In addition, the level of glial ferritin production is affected by the status of NBs, establishing a bicellular iron homeostasis. In this study, we demonstrate that glial cells are indispensable to maintain the self-renewal of NBs, unveiling a novel role of the NB glial niche during brain development.

Iron is an essential nutrient for almost all living organisms. For example, iron contributes to the replication of DNA, the generation of energy inside cells, and the transport of oxygen around the body. Iron deficiency is the most common of all nutrient deficiencies, affecting over 40% of children worldwide. This can lead to anemia and also impair how the brain and nervous system develop, potentially resulting in long-lasting cognitive damage, even after the deficiency has been treated. It is poorly understood how iron contributes to the development of the brain and nervous system. In particular, whether and how it supports nerve stem cells (or NSCs for short) which give rise to the various neural types in the mature brain. To investigate, Ma et al. experimentally reduced the levels of ferritin (a protein which stores iron) in the developing brains of fruit fly larvae. This reduction in ferritin led to lower numbers of NSCs and a smaller brain. Unexpectedly, this effect was largest when ferritin levels were reduced in glial cells which support and send signals to NSCs, rather than in the stem cells themselves. Ma et al. then used fluorescence microscopy to confirm that glial cells make and contain a lot of ferritin which can be transported to NSCs. Adding iron supplements to the diet of flies lacking ferritin did not lead to normal numbers of stem cells in the brains of the developing fruit flies, whereas adding compounds that reduce the amount of iron led to lower numbers of stem cells. Together, this suggests that ferritin transports iron from glial cells to the NSCs. Without ferritin and iron, the NSCs could not produce enough energy to divide and make new stem cells. This caused the NSCs to lose the characteristics of stem cells and prematurely turn into other types of neurons or glial cells. Together, these findings show that when iron cannot move from glial cells to NSCs this leads to defects in brain development. Future experiments will have to test whether a similar transport of iron from supporting cells to NSCs also occurs in the developing brains of mammals, and whether this mechanism applies to stem cells in other parts of the body.

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Ionizing radiation is a significant risk factor for cataracts, but the pathogenesis of radiation-induced cataracts remains incompletely understood. Ferroptosis, an iron-dependent form of programmed cell death discovered in recent years, has gained increasing attention for its role in various diseases. This article systematically reviews research progress on ionizing radiation, ferroptosis, age-related cataracts, and radiation-induced cataracts. It proposes the "ferroptosis hypothesis" for the pathogenesis of radiation-induced cataracts. Through ionization and oxidative stress effects, ionizing radiation leads to elevated free iron levels and exacerbated lipid peroxidation in lens cells, activating the ferroptosis pathway and resulting in lens opacity. The involvement of ferroptosis in the development of age-related cataracts suggests that it may also be an important pathogenic mechanism of radiation-induced cataracts. Targeting the ferroptosis pathway may be a novel strategy for preventing and treating radiation-induced cataracts. Furthermore, developing new ferroptosis-specific inhibitors with improved targeting and pharmacokinetic properties is also an essential direction for research on preventing and treating radiation-induced cataracts. The study of ferroptosis provides new insights into the mechanism and management of radiation-induced cataracts, potentially transforming radiation-induced cataracts from "inevitable" to "preventable and treatable."

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Sortilin-related receptor 1 (SorL1) deficiency is a genetic predisposition to familial Alzheimer's disease (AD), but its pathology is poorly understood. In SorL1-null rats, a disorder of the global endosome-lysosome network (ELN) is found in hippocampal neurons. Deletion of amyloid precursor protein (APP) in SorL1-null rats could not completely rescue the neuronal abnormalities in the ELN of the hippocampus and the impairment of spatial memory in SorL1-null young rats. These in vivo observations indicated that APP is one of the cargoes of SorL1 in the regulation of the ELN, which affects hippocampal-dependent memory. When SorL1 is depleted, the endolysosome takes up more of the lysosome flux and damages lysosomal digestion, leading to pathological lysosomal storage and disturbance of cholesterol and iron homeostasis in the hippocampus. These disturbances disrupt the original homeostasis of the material-energy-subcellular structure and reprogram energy metabolism based on fatty acids in the SorL1-null hippocampus, instead of glucose. Although fatty acid oxidation increases ATP supply, it cannot reduce the levels of the harmful byproduct ROS during oxidative phosphorylation, as it does in glucose catabolism. Therefore, the SorL1-null rats exhibit hippocampal degeneration, and their spatial memory is impaired. Our research sheds light on the pathology of SorL1 deficiency in AD.

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Osteoarthritis (OA) is the most prevalent degenerative joint disease, marked by cartilage degeneration, synovitis, and subchondral bone changes. The absence of effective drugs and treatments to decelerate OA's progression highlights a significant gap in clinical practice. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, has emerged as a research focus in osteoarthritic chondrocytes. This form of cell death is characterized by imbalances in iron and increased lipid peroxidation within osteoarthritic chondrocytes. Key antioxidant mechanisms, such as Glutathione Peroxidase 4 (GPX4) and the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) pathway, are vital in countering ferroptosis in osteoarthritic chondrocytes. This review collates recent findings on ferroptosis in osteoarthritic chondrocytes, emphasizing iron regulation, lipid peroxidation, and antioxidative responses. It also explores emerging therapeutics aimed at mitigating OA by targeting ferroptosis in chondrocytes.

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Iron overload is a common feature of alcoholic liver disease (ALD) and contributes significantly to disease progression. Quercetin, a flavonoid known for its iron-chelating properties, has emerged as a potential protective compound against ALD. However, research on quercetin's regulatory effects on iron levels in ALD is limited. To address this, we conducted a study using male C57BL/6J mice were subjected to a Lieber De Carli liquid diet containing ethanol (28% energy replacement) with or without quercetin supplementation (100 mg/kg.BW) for 12 weeks. Additionally, HepG2 cells, after transfection with the CYP2E1 plasmid, were incubated with ethanol and/or quercetin. Our findings revealed that ethanol consumption led to iron overload in both hepatocytes and lysosomes. Interestingly, despite the increase in iron levels, cells exhibited impaired iron utilization, disrupting normal iron metabolism. Further analysis identified a potential mechanism involving the Rab7-V1G1 (V-ATPase subunit) axis. Inhibition of V-ATPase by Concanamycin A caused elevated ROS levels, impaired lysosomal and mitochondria function, and increased expression of HIF1α and IRP2. Ultimately, this disruption in cellular processes led to iron overload and mitochondrial iron deficiency. Quercetin supplementation mitigated ethanol-induced hepatocyte damage by reversing iron overload through modulation of the Rab7-V1G1 axis and improving the interaction between lysosomes and mitochondria. In conclusion, this study elucidates a novel pathophysiological mechanism by which quercetin protects against ALD through its regulation of iron homeostasis.

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Strenuous physical training increases total blood volume (BV) through expansion of plasma (PV) and red cell volumes (RCV). In contrast, exogenous erythropoietin (EPO) treatment increases RCV but decreases PV, rendering BV stable or slightly decreased. This study aimed to determine the combined effects of strenuous training and EPO treatment on BV and markers of systemic and muscle iron homeostasis. In this longitudinal study, 8 healthy non-anemic males were treated with EPO (50 IU/kg body mass, 3x/week, subcutaneously) across 28 days of strenuous training (4d/week, exercise energy expenditures of 1334±24 kcal/d) while consuming a controlled, energy-balanced diet providing 39±4 mg/d iron. Before (PRE) and after (POST) intervention, BV compartments were measured using carbon monoxide rebreathing, and markers of iron homeostasis were assessed in blood and skeletal muscle (vastus lateralis). Training + EPO increased (p<0.01) RCV (13±6%) and BV (5±4%), whereas PV remained unchanged (p=0.86). The expansion of RCV was accompanied by a large decrease in whole-body iron stores, as indicated by decreased (p<0.01) ferritin (-77±10%) and hepcidin (-49±23%) concentrations in plasma. Training + EPO decreased (p<0.01) muscle protein abundance of ferritin (-25±20%) and increased (p<0.05) transferrin receptor (47±56%). These novel findings illustrate that strenuous training combined with EPO results in both increased total oxygen carrying capacity and hypervolemia in young healthy males. The decrease in plasma and muscle ferritin suggests that the marked upregulation of erythropoiesis alters systemic and tissue iron homeostasis, resulting in a decline in whole-body and skeletal muscle iron stores.

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Siderophores are specialized molecules produced by bacteria and fungi to scavenge iron, a crucial nutrient for growth and metabolism. Catecholate-type siderophores are mainly produced by bacteria, while hydroxamates are mostly from fungi. This study investigates the capacity of nine hydroxamate-type siderophores from fungi and Streptomyces to facilitate iron acquisition by the human pathogen Pseudomonas aeruginosa. Growth assays under iron limitation and 55Fe incorporation tests showed that all nine siderophores promoted bacterial growth and iron transport. The study also aimed to identify the TonB-dependent transporters (TBDTs) involved in iron import by these siderophores. Using mutant strains lacking specific TBDT genes, it was found that iron is imported into P. aeruginosa cells by FpvB for coprogen, triacetylfusarinine, fusigen, ferrirhodin, and ferrirubin. Iron complexed by desferioxamine G is transported by FpvB and FoxA, ferricrocin-Fe and ferrichrycin-Fe by FpvB and FiuA, and rhodotoluric acid-Fe by FpvB, FiuA, and another unidentified TBDT. These findings highlight the effectiveness of hydroxamate-type siderophores in iron transport into P. aeruginosa and provide insights into the complex molecular mechanisms involved, which are important for understanding microbial interactions and ecological balance.

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PURPOSE: Glyphosate and glyphosate-based herbicides (GBH), widely used globally, were initially considered harmless to humans. Experimental studies have suggested that these substances can disrupt iron homeostasis by interfering with iron uptake or triggering inflammatory responses. However, their potential impact on human iron homeostasis remains underexplored. APPROACH AND RESULTS: We analyzed data from 5812 participants aged three and older from the 2013 to 2018 NHANES. We investigated the relationships between urinary glyphosate levels, oral iron intake, and markers of iron homeostasis, including serum iron, unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), transferrin saturation, ferritin, and transferrin receptor. Higher urinary glyphosate levels were positively associated with oral iron intake (ß = 1.310, S.E. = 0.382, P = 0.001). A one-unit increase in the natural logarithm (ln)-glyphosate was associated with lower serum iron (ß = - 4.236, 95 % CI = - 6.432 to - 2.039, P < 0.001) and ferritin (ß = - 9.994, 95 % CI = - 17.342 to - 2.647, P = 0.009), and higher UIBC (ß = 5.431, 95 % CI = 1.061-9.800, P = 0.018) and transferrin receptor levels (ß = 0.139, 95 % CI = 0.015-0.263, P = 0.029). Increasing glyphosate exposure was associated with significant decreases in serum iron and ferritin across exposure quintiles (trend P-values = 0.003 and 0.018, respectively). CONCLUSIONS: Higher glyphosate exposure is associated with reduced iron availability, suggesting potential disruptions in iron absorption. These findings underscore the need for further research into the health implications of glyphosate exposure on iron homeostasis.

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Parkinson's disease (PD) is a common neurodegenerative disease in the older adults. The main pathological change in PD is the degenerative death of dopamine (DA) neurons in the midbrain substantia nigra, which causes a significant decrease in the DA content of the striatum. However, the exact etiology of this pathological change remains unclear. Genetic factors, environmental factors, aging, and oxidative stress may be involved in the degenerative death of dopaminergic neurons in PD. Pharmacological treatment using levodopa (L-DOPA) remains the main treatment for PD. Most patients with PD consuming L-DOPA for a long time usually develop levodopa-induced dyskinesia (LID) after 6.5 years of use, and LID seriously affects the quality of life and increases the risk of disability. Recently, studies have revealed that cerebral iron deposition may be involved in LID development and that iron deposition has neurotoxic effects and accelerates disease onset. However, the relationship between cerebral iron deposition and LID remains unclear. Herein, we reviewed the mechanisms by which iron deposition may be associated with LID development, which are mainly related to oxidative stress, neuroinflammation, and mitochondrial and lysosomal dysfunction. Using iron as an important target, the search and development of safe and effective brain iron scavengers, and thus the alleviation and treatment of LID, has a very important scientific and clinical value, as well as a good application prospect.

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BACKGROUND: Feeding milk substitutes with low iron content or whole milk without iron supplementation is considered a major factor in developing iron-deficiency anemia in neonatal dairy calves. Young calves are often supplemented with iron dextran injections on the first day of life to prevent anemia. However, the effects of preventive treatment and the presence of disease on serum iron (Fe) concentrations, serum ferritin levels, and hematological blood parameters during the early neonatal stages have not been examined in detail. Therefore, we examined and evaluated the effects of iron dextran injections and health status on the development of hematocrit (Ht), red blood cells (RBC), hemoglobin concentration (Hb), erythrocyte indices (mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration), Fe, and serum ferritin concentrations in dairy calves within the first 10 days of life. The suitability of serum ferritin as a reliable indicator of anemia in very young calves was evaluated by correlating ferritin concentrations with known laboratory diagnostic parameters of anemia. RESULTS: Iron supplementation significantly increased Fe levels (P = 0.048) but did not affect serum ferritin levels in neonatal calves. Fe concentrations were significantly lower in diseased than healthy calves (P = 0.0417). Iron supplementation significantly affected the health status, as observed in Ht (Ptreat=0.0057; Phealth=0.0097), RBC (Ptreat=0.0342; Phealth=0.0243), and Hb (Ptreat=0.0170; Phealth=0.0168). Serum ferritin levels did not significantly correlate with Fe levels. Both groups showed marked differences in ferritin levels, with the highest levels measured on day 2. Fe concentrations showed weak negative correlations with Hb and Ht levels on day 3 (ρ=-0.45; P = 0.0034 and ρ=-0.045; P = 0.0032, respectively). RBC count showed strong positive correlations with Hb and Ht levels (ρ = 0.91 and ρ = 0.93; P < 0.001). CONCLUSION: Iron dextran injections increased Fe concentrations but reduced Ht level, RBC count, and Hb level. The presence of diseases led to a reduction in Fe and higher values of Ht, RBC, and Hb in moderate disease than in severe disease. Due to physiological fluctuations during the first 3 days of life, serum ferritin level seems unuseful for evaluating iron storage before day 4 of life.

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Staphylococcus aureus is a major contributor to bacterial-associated mortality, owing to its exceptional adaptability across diverse environments. Iron is vital to most organisms but can be toxic in excess. To manage its intracellular iron, S. aureus, like many pathogens, employs intricate systems. We have recently identified IsrR as a key regulatory RNA induced during iron starvation. Its role is to reduce the synthesis of non-essential iron-containing proteins under iron-depleted conditions. In this study, we unveil IsrR's regulatory action on MiaB, an enzyme responsible for methylthio group addition to specific sites on transfer RNAs (tRNAs). We use predictive tools and reporter fusion assays to demonstrate IsrR's binding to the Shine-Dalgarno sequence of miaB RNA, thereby impeding its translation. The effectiveness of IsrR hinges on the integrity of a specific C-rich region. As MiaB is non-essential and has iron-sulfur clusters, IsrR induction spares iron by downregulating miaB. This may improve S. aureus fitness and aid in navigating the host's nutritional immune defenses.IMPORTANCEIn many biotopes, including those found within an infected host, bacteria confront the challenge of iron deficiency. They employ various strategies to adapt to this scarcity of nutrients, one of which involves regulating iron-containing proteins through the action of small regulatory RNAs. Our study shows how IsrR, a small RNA from S. aureus, prevents the production of MiaB, a tRNA-modifying enzyme containing iron-sulfur clusters. With this illustration, we propose a new substrate for an iron-sparing small RNA, which, when downregulated, should reduce the need for iron and save it to essential functions.

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Throughout the world, some foods and feeds commonly consumed by humans and animals are inadvertently contaminated with mycotoxins. Zearalenone (ZEA) is a typical environmental/food contaminant that can cause varying degrees of damage to the body, such as reproductive toxicity, hepatotoxicity, immunotoxicity, etc. It poses a serious threat to the living environment and human and animal health. Increasing evidence shows that mycotoxin-induced organ damage may be closely related to ferroptosis. However, the mechanism of ZEA-induced liver injury is still not fully understood. Therefore, this study aimed to explore whether ZEA can trigger ferroptosis in the liver and cause liver injury. This study was conducted by establishing in vivo and in vitro ZEA exposure models. The results showed that ZEA exposure led to typical liver injury indicators. ZEA inhibited the Nrf2/keap1 antioxidant signaling pathway, aggravated the oxidative stress response, and inhibited the body's antioxidant function. Additionally, it was found that ZEA can aggravate lipid peroxidation by blocking the system Xc-/GSH/GPX4 axis, upregulating the protein expression of ACSL4, and affecting the import, storage, and export of iron ions, thereby inducing iron ion metabolism disorders. A combination of multiple factors induces ferroptosis in mouse liver and AML12 cells. Pretreatment with deferoxamine, an inhibitor of ferroptosis, can alleviate ferroptosis damage induced by ZEA, indicating the crucial role of ferroptosis in cell damage caused by ZEA. This study deeply explores the hepatic ferroptosis pathway induced by ZEA, provides a new theoretical basis for ZEA-induced hepatotoxicity, and offers new insights for exploring potential treatment strategies.

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Iron homeostasis is essential for maintaining metabolic health and iron disorder has been linked to chronic metabolic diseases. Increasing thermogenic capacity in adipose tissue has been considered as a potential approach to regulate energy homeostasis. Both mitochondrial biogenesis and mitochondrial function are iron-dependent and essential for adipocyte thermogenic capacity, but the underlying relationships between iron accumulation and adipose thermogenesis is unclear. Firstly, we confirmed that iron homeostasis and the iron regulatory markers (e.g., Tfr1 and Hfe) are involved in cold-induced thermogenesis in subcutaneous adipose tissues using RNA-seq and bioinformatic analysis. Secondly, an Hfe (Hfe-/-)-deficient mouse model, in which tissues become overloaded with iron, was employed. We found iron accumulation caused by Hfe deficiency enhanced mitochondrial respiratory chain expression in subcutaneous white adipose in vivo and resulted in enhanced tissue thermogenesis with upregulation of PGC-1α and adipose triglyceride lipase, mitochondrial biogenesis and lipolysis. To investigate the thermogenic capacity in vitro, stromal vascular fraction from adipose tissues was isolated, followed with adipogenic differentiation. Primary adipocyte from Hfe-/- mice exhibited higher cellular oxygen consumption, associated with enhanced expression of mitochondrial oxidative respiratory chain protein, while primary adipocytes or stromal vascular fractions from WT mice supplemented with iron citrate) exhibited similar effect in thermogenic capacity. Taken together, these findings indicate iron supplementation and iron accumulation (Hfe deficiency) can regulate adipocyte thermogenic capacity, suggesting a potential role for iron homeostasis in adipose tissues.

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Zhigancao decoction is a traditional prescription for treating irregular pulse and palpitations in China. As the monarch drug of Zhigancao decoction, the bioactive molecules of licorice against heart diseases remain elusive. We established the HRESIMS-guided method leading to the isolation of three novel bicyclic peptides, glycnsisitins A-C (1-3), with distinctive C-C and C-O-C side-chain-to-side-chain linkages from the roots of Glycyrrhiza uralensis (Licorice). Glycnsisitin A demonstrated stronger cardioprotective activity than glycnsisitins B and C in an in vitro model of doxorubicin (DOX)-induced cardiomyocyte injury. Glycnsisitin A treatment not only reduced the mortality of heart failure (HF) mice in a dose-dependent manner but also significantly attenuated DOX-induced cardiac dysfunction and myocardial fibrosis. Gene set enrichment analysis (GSEA) of the differentially expressed genes indicated that the cardioprotective effect of glycnsisitin A was mainly attributed to its ability to maintain iron homeostasis in the myocardium. Mechanistically, glycnsisitin A interacted with transferrin and facilitated its binding to the transferrin receptor (TFRC), which caused increased uptake of iron in cardiomyocytes. These findings highlight the key role of bicyclic peptides as bioactive molecules of Zhigancao decoction for the treatment of HF, and glycnsisitin A constitutes a promising therapeutic agent for the treatment of HF.

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Hepcidin has a crucial role in iron homeostasis upon inflammatory conditions such as inflammatory bowel disease (IBD). Thus, we conducted a systematic review and meta-analysis to determine the overall association between serum hepcidin concentrations and IBD. Based on the preferred reporting items for systematic review and meta-analysis (PRISMA) protocols, an electronic literature search was conducted on PubMed/MEDLINE, Scopus, and Web of Science until June 2020. Studies were deemed eligible for inclusion if they met the following criteria: (1) diagnosis of IBD, (2) observational design, and (3) measured serum hepcidin and prohepcidin concentrations in IBD patients and control group. Overall, 10 studies including 1184 participants were evaluated. Random-effects meta-analysis revealed that subjects with IBD had 7.22 ng/mL (95% CI: 2.10, 12.34; p = .006) higher serum hepcidin concentrations compared to control groups. A nonsignificantly lower serum prohepcidin concentration (0.522 ng/mL, 95% CI: -1.983 to 0.939; p = .484) was found for IBD patients compared to healthy subjects. However, there was significant heterogeneity among the studies regarding both hepcidin (I 2 = 98%, p < .001) and prohepcidin levels (I 2 = 96%, p < .001), respectively. In an age-based subgroup analysis, patients aged ≥18 years with IBD displayed higher serum hepcidin levels when compared to healthy individuals (22.36 ng/mL, 95% CI, 2.12-42.61; p = .030). Hepcidin concentrations are elevated in subjects with IBD; however, the clinical relevance of this finding requires further evaluation in future investigations as the increase is relatively small compared to the wide range of normal hepcidin values.

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The role of iron dyshomeostasis in neurodegenerative disease has implicated the involvement of genes that regulate brain iron. The homeostatic iron regulatory gene (HFE) has been at the forefront of these studies given the role of the H63D variant (H67D in mice) in increasing brain iron load. Despite iron's role in oxidative stress production, H67D mice have shown robust protection against neurotoxins and improved recovery from intracerebral hemorrhage. Previous data support the notion that H67D mice adapt to the increased brain iron concentrations and hence develop a neuroprotective environment. This adaptation is particularly evident in the lumbar spinal cord (LSC) and ventral midbrain (VM), both relevant to neurodegeneration. We studied C57BL6/129 mice with homozygous H67D compared to WT HFE. Immunohistochemistry was used to analyze dopaminergic (in the VM) and motor (in the LSC) neuron population maturation in the first 3 months. Immunoblotting was used to measure protein carbonyl content and the expression of oxidative phosphorylation complexes. Seahorse assay was used to analyze metabolism of mitochondria isolated from the LSC and VM. Finally, a Nanostring transcriptomic analysis of genes relevant to neurodegeneration within these regions was performed. Compared to WT mice, we found no difference in the viability of motor neurons in the LSC, but the dopaminergic neurons in H67D mice experienced significant decline before 3 months of age. Both regions in H67D mice had alterations in oxidative phosphorylation complex expression indicative of stress adaptation. Mitochondria from both regions of H67D mice demonstrated metabolic differences compared to WT. Transcriptional differences in these regions of H67D mice were related to cell structure and adhesion as well as cell signaling. Overall, we found that the LSC and VM undergo significant and distinct metabolic and transcriptional changes in adaptation to iron-related stress induced by the H67D HFE gene variant.

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Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a lipid-binding protein that occurs in large quantities in human blood plasma, and a polymorphism of the APOE gene locus has been identified as risk factors for AD. The human genome involves three major APOE alleles (APOE2, APOE3, APOE4), which encode for three subtly distinct apolipoprotein E isoforms (APOE2, APOE3, APOE4). The canonic function of these apolipoproteins is lipid transport in blood and brain, but APOE4 allele carriers have a much higher risk for AD. In fact, about 60% of clinically diagnosed AD patients carry at least one APOE4 allele in their genomes. Although the APOE4 protein has been implicated in pathophysiological key processes of AD, such as extracellular beta-amyloid (Aß) aggregation, mitochondrial dysfunction, neuroinflammation, formation of neurofibrillary tangles, modified oxidative lipid metabolism, and ferroptotic cell death, the underlying molecular mechanisms are still not well understood. As for all mammalian cells, iron plays a crucial role in neuronal functions and dysregulation of iron homeostasis has also been implicated in the pathogenesis of AD. Imbalances in iron homeostasis and impairment of the hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to neuronal ferroptosis. In this review, we summarize the current knowledge on APOE4-related oxidative lipid metabolism and the potential role of ferroptosis in the pathogenesis of AD. Pharmacological interference with these processes might offer innovative strategies for therapeutic interventions.

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Neurodegenerative diseases represent a pressing global health challenge, and the identification of novel mechanisms underlying their pathogenesis is of utmost importance. Ferroptosis, a non-apoptotic form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a pivotal player in the pathogenesis of neurodegenerative diseases. This review delves into the discovery of ferroptosis, the critical players involved, and their intricate role in the underlying mechanisms of neurodegeneration, with an emphasis on Alzheimer's and Parkinson's diseases. We critically appraise unsolved mechanistic links involved in the initiation and propagation of ferroptosis, such as a signaling cascade resulting in the de-repression of lipoxygenase translation and the role played by mitochondrial voltage-dependent anionic channels in iron homeostasis. Particular attention is given to the dual role of heme oxygenase in ferroptosis, which may be linked to the non-specific activity of P450 reductase in the endoplasmic reticulum. Despite the limited knowledge of ferroptosis initiation and progression in neurodegeneration, Nrf2/Bach1 target genes have emerged as crucial defenders in anti-ferroptotic pathways. The activation of Nrf2 and the inhibition of Bach1 can counteract ferroptosis and present a promising avenue for future therapeutic interventions targeting ferroptosis in neurodegenerative diseases.

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Sepsis, marked by organ dysfunction, necessitates reliable biomarkers. Ribonuclease inhibitor 1 (RNH1), a ribonuclease (RNase) inhibitor, emerged as a potential biomarker for acute kidney injury and mortality in thoracoabdominal aortic aneurysm patients. Our study investigates RNH1 dynamics in sepsis, its links to mortality and organ dysfunction, and the interplay with RNase 1 and RNase 5. Furthermore, we explore RNH1 as a therapeutic target in sepsis-related processes like inflammation, non-canonical inflammasome activation, and iron homeostasis. We showed that RNH1 levels are significantly higher in deceased patients compared to sepsis survivors and correlate with creatine kinase, aspartate and alanine transaminase, bilirubin, serum creatinine and RNase 5, but not RNase 1. RNH1 mitigated LPS-induced TNFα and RNase 5 secretion, and relative mRNA expression of ferroptosis-associated genes HMOX1, FTH1 and HAMP in PBMCs. Monocytes were identified as the predominant type of LPS-positive PBMCs. Exogenous RNH1 attenuated LPS-induced CASP5 expression, while increasing IL-1ß secretion in PBMCs and THP-1 macrophages. As RNH1 has contradictory effects on inflammation and non-canonical inflammasome activation, its use as a therapeutic agent is limited. However, RNH1 levels may play a central role in iron homeostasis during sepsis, supporting our clinical observations. Hence, RNH1 shows promise as biomarkers for renal and hepatic dysfunction and hepatocyte injury, and may be useful in predicting the outcome of septic patients.

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