Ferroptosis is a type of iron‑dependent cell death characterized by excessive lipid peroxidation and may serve as a potential therapeutic target in cancer treatment. While the mechanisms governing ferroptosis continue to be explored and elucidated, an increasing body of research highlights the significant impact of epigenetic modifications on the sensitivity of cancer cells to ferroptosis. Epigenetic processes, such as DNA methylation, histone modifications and non‑coding RNAs, have been identified as key regulators that modulate the expression of ferroptosis‑related genes. These alterations can either enhance or inhibit the sensitivity of gastrointestinal cancer (GIC) cells to ferroptosis, thereby affecting the fate of GICs. Drugs that target epigenetic markers for advanced‑stage cancer have shown promising results in enhancing ferroptosis and inhibiting tumor growth. This review explores the intricate relationship between epigenetic regulation and ferroptosis in GICs. Additionally, the potential of leveraging epigenetic modifications to trigger ferroptosis in GICs is investigated. This review highlights the importance of further research to elucidate the specific mechanisms underlying epigenetic control of ferroptosis and to advance the development of novel therapeutic approaches.

Patients with chronic inflammation are burdened with anemia of inflammation (AI), where inflammatory cytokines inhibit erythropoiesis, impede erythropoietin production, and limit iron availability by inducing the iron regulator hepcidin. High hepcidin hinders iron absorption and recycling, thereby worsening the impaired erythropoiesis by restricting iron availability. AI management is important as anemia impacts quality of life and potentially affects morbidity and mortality. The bone morphogenetic protein (BMP)-SMAD pathway is crucial for hepcidin regulation. Here, we characterized a research antibody against BMP receptor ALK2, RKER-216, and investigated its mechanism in suppressing hepcidin and improving anemia in acute/chronic inflammation. Additive effects of RKER-216 and recombinant human erythropoietin (rhEPO) on erythropoiesis and iron utilization were also explored. We showed that RKER-216 neutralized ALK2 activity by competing with the binding of BMP6. RKER-216 reduced hepcidin transcription in Hep3B cells, and a subcutaneous dose of RKER-216 at 3 mg/kg suppressed serum hepcidin and increased circulating iron for 3-4 days in wildtype mice. Moreover, RKER-216 decreased hepcidin by inhibiting SMAD1/5/9 signaling in lipopolysaccharide-mediated inflammation and liberated iron from the recycling pathway to alleviate anemia in mice with adenine-induced chronic kidney disease (CKD), a mouse model of AI. Finally, RKER-216 reversed iron-restricted erythropoiesis in CKD mice and supplied the iron requirement for complete resolution of anemia when coupled with rhEPO in addressing AI. Our data support that ALK2 is a key hepcidin regulator and that a neutralizing ALK2 antibody has the potential to restore iron homeostasis as monotherapy or in combination with rhEPO to ameliorate AI.

This study aimed to report the effects of chronic exposure of zebrafish exposed to environmentally relevant concentrations of 0.5, 2.4, and 5.0 mg L-1 iron (Fe) and 0.2, 0.4, and 2.0 mg L-1 aluminum (Al). We also evaluated the reversal and generational transposition (F1) of possible histopathological, behavioral, and genotoxic changes in the species. Locomotion changes that may have been caused by the increase in the number of apoptotic cells and in the telencephalic mitochondrial activity were observed especially after the 30 days exposure to Al and persisted after recovery (30 days). We also observed histopathological changes, such as an increase in the number of intestinal goblet cells, even after the recovery period in these animals. Our results also showed that the Fe concentrations used were insufficient to cause genotoxicity, behavioral and intestinal epithelium changes. The adult offspring (F1) of animals exposed to Al showed changes in locomotion and in the amount of goblet cells, demonstrating that even in low concentrations this pollutant can harm subsequent generations in the aquatic biota. Animals demonstrate, in general, greater tolerance to Fe which may be related to the physiological demand of this metal by the body. Even so, all concentrations of both metals that caused some change in the species represent Brazilian environmental occurrences or Brazilian legislation. It highlights the need for updating the guidelines and constant monitoring of aquatic environments, since even in the face of a hypothetical decontamination of the environment, some changes could persist and affect different trophic levels.

The transferrin receptor (TfR) is one of the key proteins involved in cellular iron uptake. TfR-mediated endocytosis of transferrin-bound iron is the major pathway for iron acquisition by most cells in the body. Over the past three decades, the studies on TfR have made significant progress, and also, our knowledge on cell iron uptake has greatly been improved. Here we focus on recent advances in the studies on TfR and a brief discussion of the structures and functions of four different types of TfR, namely TfR1 (transferrin receptor 1), TfR2 (transferrin receptor 2), TfR3 (glyceraldehyde-3-phosphate dehydrogenase) and TfR4 (cubilin). These proteins work in different cells or organs and at different times, ensuring that cells and tissues get the iron they need. Their normal expression and function are fundamental to the body's iron homeostasis.

A series of spiroisatin-based hydrazide conjugates IV(a-t) was synthesized and structurally characterized using spectral data, with compound IV-a further confirmed by x-ray diffraction analysis. All the synthesized compounds were evaluated for their biological potential in a cell painting assay. Among the synthesized spiroisatin derivatives, compound IV-p exhibited significant activity in inducing cellular morphological changes, with an induction value of 30.6%. In addition, some compounds showed high biosimilarities with marketed drugs. Specifically, the compounds IV-n and IV-p showed a high biosimilarity with the orally active iron chelator deferasirox, and IV-m showed a high biosimilarity with the kinase inhibitor alisertib. Furthermore, compounds IV-p showed significant inhibition against human breast cancer (MDA-MB-231 = 82.37%) and colorectal carcinoma cell lines (HCT-116 = 86.25%) during preliminary investigations. Moreover, it was revealed through molecular docking analysis that IV-p possesses a good binding score against ferroportin and Aurora A kinase (-9.3 and -9.2 kcal/mol), which are quite comparable with the deferasirox (-9.2 kcal/mol) and alisertib (-9.8 kcal/mol). Pharmacokinetic studies revealed that the synthesized conjugates have good oral bioavailability, balanced hydrophilicity, and minimal toxicity. The results of this study clearly highlight the potential of these conjugates as promising small bioactive molecules.

A local disruption of iron homeostasis leading to oxidative stress is considered one of the main mechanisms of asbestos-related genotoxicity. Another aspect contributing to the risk of developing pathological consequences upon asbestos exposure is individual genetic factors. In a previous study, we identified a coding SNP in the hephaestin gene (HEPH) that protects against developing asbestos-related thoracic cancer. Heph is a ferroxidase that promotes iron export in concert with the permease ferroportin (Fpn1). Here, we performed an in-depth functional characterization of the HephD568H variant to gain insights into the molecular basis of its protective activity. We showed that HephD568H forms a complex with Fpn1 and possesses full ferroxidase activity. Although HephD568H is more efficiently recruited to the plasma membrane, it is impaired in binding iron-deficient Tfn, whose interaction with wild-type (WT) ferroxidase emerged as a novel mechanism to perceive brain iron needs. Heph is expressed in the human lung by pericytes and fibroblasts, and lung pericytes were shown to respond to iron demand by upregulating the iron exporter pair. These results extend the paradigm of local iron regulation discovered at the blood-brain barrier to the pulmonary vasculature. Furthermore, they establish a mechanistic link between changes in iron sensing and the risk of developing asbestos-related malignancies.

Iron homeostasis is key to both the survival of virtually all organisms and the virulence of fungi including Aspergillus fumigatus, a human fungal pathogen causing life-threatening invasive infections. Unlike the extensively studied fungal species Saccharomyces cerevisiae and Schizosaccharomyces pombe, A. fumigatus encodes an uncharacterized homolog of vertebrate ferroportin (Fpn1), termed FpnA. Fpn1 is the only known vertebrate iron efflux transporter, while microbial organisms are thought to lack iron efflux systems. After correcting the exon-intron annotation, inactivation and conditional overexpression of the A. fumigatus FpnA-encoding gene (fpnA) indicated, that FpnA mediates resistance to nickel, cobalt and gallium but not to iron, aluminium, cadmium, copper or zinc. Functional N-terminal tagging with a fluorescent protein demonstrated localization of FpnA in the vacuolar membrane, suggesting that FpnA detoxifies substrate metals by vacuolar deposition. In line, overexpression of fpnA reduced the utilization of urea as a nitrogen source, most likely by depriving cytosolic urease of its essential cofactor nickel. Phylogenetic analysis illustrated conservation of FpnA in all fungal divisions and several other eukaryotic lineages, underlining its crucial role in metal homeostasis. The divergent localization and functionalization of ferroportin homologs in two phylogenetic sister groups, metazoa and fungi, is of particular evolutionary interest.

Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disease with multiple tissue damage. However, the pathology remains elusive, and effective treatments are lacking. Multiple types of programmed cell death (PCD) implicated in SLE progression have recently been identified. Although ferroptosis, an iron-dependent form of cell death, has numerous pathophysiological features similar to those of SLE, such as intracellular iron accumulation, mitochondrial dysfunction, lipid metabolism disorders and concentration of damage associated-molecular patterns (DAMPs), only a few reports have demonstrated that ferroptosis is involved in SLE progression and that the role of ferroptosis in SLE pathogenesis continues to be neglected. Therefore, this review elucidates the potential intricate relationship between SLE and ferroptosis to provide a reliable theoretical basis for further research on ferroptosis in the pathogenesis of SLE.

Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species are defined by their genomes, and differences between individuals within a given species directly result from variations in their genetic codes. While genetic alterations can give rise to disease-causing acquisitions of distinct cell identities, it is now well-established that biochemical imbalances within a cell can also lead to cellular dysfunction and diseases. Specifically, nongenetic chemical events orchestrate cell metabolism and transcriptional programs that govern functional cell identity. Thus, imbalances in cell signaling, which broadly defines the conversion of extracellular signals into intracellular biochemical changes, can also contribute to the acquisition of diseased cell states. Metal ions exhibit unique chemical properties that can be exploited by the cell. For instance, metal ions maintain the ionic balance within the cell, coordinate amino acid residues or nucleobases altering folding and function of biomolecules, or directly catalyze specific chemical reactions. Thus, metals are essential cell signaling effectors in normal physiology and disease. Deciphering metal ion signaling is a challenging endeavor that can illuminate pathways to be targeted for therapeutic intervention. Here, we review key cellular processes where metal ions play essential roles and describe how targeting metal ion signaling pathways has been instrumental to dissecting the biochemistry of the cell and how this has led to the development of effective therapeutic strategies.

Transport of iron across the cell membrane is a tightly controlled process carried out by specific proteins in all living cells. In yeast and in mammals, a system formed by an enzyme with ferroxidase activity coupled to a membrane transporter supports iron uptake or iron efflux, respectively. Ferroxidase belongs to the family of blue multicopper oxidases, enzymes able to couple the one-electron oxidation of substrate(s) to full reduction of molecular oxygen to water. On the other hand, the permeases are widely different and are specific to Fe3+ and Fe2+ in yeast and multicellular organisms, respectively. This review will describe the yeast and human ferroxidase-permease systems, highlighting similarities and differences in structure, function and regulation of the respective protein components.

Iron plays a crucial role through various life stages of human. Iron homeostasis is primarily regulated by iron absorption which is mediated via divalent metal-ion transporter 1 (DMT1), and iron export protein ferroportin (FPN), as there is no active pathway for iron excretion from the body. Recent studies have shown that the magnitude of iron absorption changes through various life stages to meet changing iron requirements.

This review aims to provide an overview of recent researches on the regulation of iron absorption throughout mammalian life cycle, with the potential to reveal novel molecules and pathways at special stage of life. Such insights may pave the way for new treatments for disorders associated with aberrant iron homeostasis in the future.

This review first summarize the mechanism and regulation of iron absorption throughout various life stages, highlighting that regulatory mechanisms have developed to precisely align iron absorption to iron requirements. In adults, iron absorption is enhanced when body is deficient of iron, conversely, iron absorption is reduced when iron demand decreases via systemic regulator Hepcidin and cellular regulation. In the elderly, age-related inflammation, hormonal changes, and chronic diseases may affect the production of Hepcidin, affecting iron absorption. In infants, intestinal iron absorption and its regulatory mechanism are different from that in adults and there might be an alternative pathway independent of DMT1 and FPN due to high iron absorption. Unique to the fetus, iron is absorbed from maternal stores for its own use through the placenta and is regulated by maternal iron status. This review also proposes directions for further studies, offering promising avenues for developing new treatments for disorders associated with aberrant iron homeostasis.

Iron is a potent biochemical, and accurate homeostatic control is orchestrated by a network of interacting players at multiple levels. Although our understanding of organismal iron homeostasis has advanced, intracellular iron homeostasis is poorly understood, including coordination between organelles and iron export into the ER/Golgi. Here, we show that SLC39A13 (ZIP13), previously identified as a zinc transporter, promotes intracellular iron transport and reduces intracellular iron levels. ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular compartments, such as lysosomes and mitochondria, as well as elevating iron in the cytosol. ZIP13 overexpression has the opposite effect, increasing iron in organellar compartments. We suggest that ZIP13 gatekeeps an iron trafficking route that shunts iron from the cytosol to the ER/Golgi hub. Zip13-knockout male mice have iron deposition in several tissues. These data demonstrate that mammalian ZIP13 is crucial for iron homeostasis and suggest a potential iron transport function.

Iron deficiency is globally prevalent, causing an array of developmental, haematological, immunological, neurological, and cardiometabolic impairments, and is associated with symptoms ranging from chronic fatigue to hair loss. Within cells, iron is utilised in a variety of ways by hundreds of different proteins. Here, we review links between molecular activities regulated by iron and the pathophysiological effects of iron deficiency. We identify specific enzyme groups, biochemical pathways, cellular functions, and cell lineages that are particularly iron dependent. We provide examples of how iron deprivation influences multiple key systems and tissues, including immunity, hormone synthesis, and cholesterol metabolism. We propose that greater mechanistic understanding of how cellular iron influences physiological processes may lead to new therapeutic opportunities across a range of diseases.

Significance: Ferroptosis, a form of regulated cell death characterized by a large amount of lipid peroxidation-mediated membrane damage, joins the evolution of multisystem diseases, for instance, neurodegenerative diseases, chronic obstructive pulmonary disease, acute respiratory distress syndrome, osteoporosis, osteoarthritis, and so forth. Since being identified as the third gasotransmitter in living organisms, the intricate role of hydrogen sulfide (H2S) in ferroptosis has emerged at the forefront of research. Recent Advances: Novel targets in the relevant metabolic pathways have been found, including transferrin receptor 1, cystine/glutamate antiporter, and others, coupled with the exploration of new signaling pathways, particularly the p53 signaling pathway, the nitric oxide/nuclear factor erythroid 2-related factor 2 signaling pathway, and so on. Many diseases such as emphysema and airway inflammation, myocardial diseases, endothelial dysfunction in aging arteries, and traumatic brain injury have recently been found to be alleviated directly by H2S inhibition of ferroptosis. Safe, effective, and tolerable novel H2S donors have been developed and have shown promising results in phase I clinical trials. Critical Issues: Complicated cross talk between the ferroptosis signaling pathway and oncogenic factors results in the risk of cancer when inhibiting ferroptosis. Notably, targeted delivery of H2S is still a challenging task. Future Directions: Discovering more reliable and stable novel H2S donors and achieving their targeted delivery will enable further clinical trials for diseases associated with ferroptosis inhibition by H2S, determining their safety, efficacy, and tolerance. Antioxid. Redox Signal. 41, 1150-1172.

Mycobacterium avium subsp. paratuberculosis (MAP) is known to cause paratuberculosis. One notable protein, MAP3773c, plays a critical role in iron metabolism as a transcription factor. This study aims to investigate the binding affinity of MAP3773c to the chromatin of the Ferroportin1 (FPN1) gene in murine macrophage J774 A.1. We conducted a sequence alignment to identify potential interaction sites for MAP3773c. Following this, we used in silico analysis to predict binding interactions, complemented by electrophoretic mobility shift assay (EMSA) to confirm in vitro binding of MAP3773c. The map3773c gene was cloned into the pcDNA3.1 vector, with subsequent expression analysis carried out via Western blotting and real-time PCR. Chromatin immunoprecipitation (CHiP) assays were performed on transfected macrophages to confirm binding in the native chromatin context. Our in silico and in vitro analysis indicated that MAP3773c interacts with two binding motifs within the FPN1 coding region. The ChiP results provided additional validation, demonstrating the binding of MAP3773c to the FPN1 chromatin through successful amplification of the associated chromatin fragment via PCR. Our study demonstrated that MAP3773c binds to FPN1 and provides insight into the role of MAP3773c and its effect on host iron transport.

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.

Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver's susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.

Osteoarthritis (OA) is a prevalent degenerative disease in elderly people that is characterized by cartilage loss and abrasion, leading to joint pain and dysfunction. The aetiology of OA is complicated and includes abnormal mechanical stress, a mild inflammatory environment, chondrocyte senescence and apoptosis, and changes in chondrocyte metabolism. Ferroptosis is a regulated cell death modality characterized by the excessive accumulation of lipid peroxidation and mitochondrial dysfunction. The role of ferroptosis in OA pathogenesis has aroused researchers' attention in the past two years, and there is mounting evidence indicating that ferroptosis is destructive. However, the impact of ferroptosis on OA and how the regulators of ferroptosis affect OA development are unclear. Here, we reviewed the current understanding of ferroptosis in OA pathogenesis and summarized several drugs and compounds targeting ferroptosis in OA treatment. The accumulation of intracellular iron, the trigger of Fenton reaction, the excessive production of ROS, the peroxidation of PUFA-PLs, and mitochondrial and membrane damage are involved in chondrocyte ferroptosis. System Xc - and GPX4 are the most important regulators that control ferroptosis. Several compounds, such as DFO and Fer-1, have been proven effective in preventing ferroptosis and slowing OA progression on animal models. Collectively, targeting ferroptosis shows great potential in treating OA.

Parkinson's disease (PD) is a prevalent and advancing age-related neurodegenerative disorder, distinguished by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Iron regional deposit in SNpc is a significant pathological characteristic of PD. Brain iron homeostasis is precisely regulated by iron metabolism related proteins, whereas disorder of these proteins can damage neurons and glial cells in the brain. Additionally, growing studies have reported iron metabolism related proteins are involved in the ferroptosis progression in PD. However, the effect of these proteins in the ferroptosis of PD has not been systematically summarized. This review focuses on the roles of iron metabolism related proteins in the ferroptosis of PD. Finally, we put forward the iron early diagnosis according to the observation of iron deposits in the brain and showed the recent advances in iron chelation therapy in PD.

Although research on the role of iron in host immunity has a history spanning decades, it is only relatively recently that attention has been directed toward the biological effects of iron on the intestinal mucus layer, prompted by an evolving understanding of the role of this material in immune defense. The mucus layer, secreted by intestinal goblet cells, covers the intestinal epithelium, and given its unique location, interactions between the host and gut microbiota, as well as among constituent microbiota, occur frequently within the mucus layer. Iron, as an essential nutrient for the vast majority of life forms, regulates immune responses from both the host and microbial perspectives. In this review, we summarize the iron metabolism of both the host and gut microbiota and describe how iron contributes to intestinal mucosal homeostasis via the intestinal mucus layer with respect to both host and constituent gut microbiota. The findings described herein offer a new perspective on iron-mediated intestinal mucosal barrier function.

The maternal-to-zygotic transition is crucial in embryonic development, marked by the degradation of maternally provided mRNAs and initiation of zygotic gene expression. However, the changes occurring at the protein level during this transition remain unclear. Here, we conducted protein profiling throughout zebrafish embryogenesis using quantitative mass spectrometry, integrating transcriptomics and translatomics datasets. Our data show that, unlike RNA changes, protein changes are less dynamic. Further, increases in protein levels correlate with mRNA translation, whereas declines in protein levels do not, suggesting active protein degradation processes. Interestingly, proteins from pure zygotic genes are present at fertilization, challenging existing mRNA-based gene classifications. As a proof of concept, we utilized CRISPR-Cas13d to target znf281b mRNA, a gene whose protein significantly accumulates within the first 2 h post-fertilization, demonstrating its crucial role in development. Consequently, our protein profiling, coupled with CRISPR-Cas13d, offers a complementary approach to unraveling maternal factor function during embryonic development.

Ferroportin (Fpn) is the only known iron exporter and plays an essential role in iron homeostasis. Serum concentrations of Fpn in health and/or diseased states are still mostly unknown. Therefore, the aim of this study was to determine the concentration of Fpn in the serum of women of reproductive age (WRA) for the first time, and to establish whether there is a difference in the concentration of Fpn according to ferritin status.

This research included 100 WRA (18-45 years, C-reactive protein (CRP) < 5 mg/L, hemoglobin > 120 g/L). Serum Fpn was measured using Enzyme Linked Immunosorbent Assay (ELISA) method on the analyzer EZ Read 800 Plus (Biochrom, Cambridge, UK). Reference interval was calculated using the robust method.

The median concentration of Fpn in the whole study group was 9.74 (5.84-15.69) µg/L. The subgroup with ferritin concentration > 15 µg/L had a median Fpn concentration 15.21 (10.34-21.93) µg/L, which significantly differed from Fpn concentration in the subgroup with ferritin concentration ≤ 15 µg/L (5.93 (4.84-8.36) µg/L, P < 0.001). The reference limits for the Fpn were 2.26-29.81 µg/L with 90% confidence intervals (CI) of 1.78 to 2.83 and 25.37 to 34.33, respectively.

The proposed reference interval could help in the future research on iron homeostasis both in physiological conditions and in various disorders, because this is the first study that measured Fpn concentration in a certain gender and age group of a healthy population.

IL-1β represents an important inflammatory factor involved in the host response against GBS infection. Prior research has suggested a potential involvement of IL-1β in the process of ferroptosis. However, the relationship between IL-1β and ferroptosis in the context of anti-GBS infection remains uncertain. This research demonstrates that the occurrence of ferroptosis is essential for the host's defense against GBS infection in a mouse model of abdominal infection, with peritoneal macrophages identified as the primary cells undergoing ferroptosis. Further research indicates that IL-1β induces lipid oxidation in macrophages through the upregulation of pathways related to lipid oxidation. Concurrently, IL-1β is not only involved in the initiation of ferroptosis in macrophages, but its production is intricately linked to the onset of ferroptosis. Ultimately, we posit that ferroptosis acts as a crucial initiating factor in the host response to GBS infection, with IL-1β playing a significant role in the resistance to infection by serving as a key inducer of ferroptosis.

Ferroptosis, an iron-dependent form of non-apoptotic regulated cell death, is induced by the accumulation of lipid peroxides on cellular membranes. Over the past decade, ferroptosis has emerged as a crucial process implicated in various physiological and pathological systems. Positioned as an alternative modality of cell death, ferroptosis holds promise for eliminating cancer cells that have developed resistance to apoptosis induced by conventional therapeutics. This has led to a growing interest in leveraging ferroptosis for cancer therapy across diverse malignancies. Gliomas are tumors arising from glial or precursor cells, with glioblastoma (GBM) being the most common malignant primary brain tumor that is associated with a dismal prognosis. This review provides a summary of recent advancements in the exploration of ferroptosis-sensitizing methods, with a specific focus on their potential application in enhancing the treatment of gliomas. In addition to summarizing the therapeutic potential, this review also discusses the intricate interplay of ferroptosis and its potential tumor-promoting roles within gliomas. Recognizing these dual roles is essential, as they could potentially complicate the therapeutic benefits of ferroptosis. Exploring strategies aimed at circumventing these tumor-promoting roles could enhance the overall therapeutic efficacy of ferroptosis in the context of glioma treatment.

In fish, the gill plays a vital role in regulating the absorption of trace metals and is also highly susceptible to metal toxicity. Trace metals such as iron (Fe), copper (Cu), zinc (Zn), and manganese (Mn) are involved in various catalytic activities and molecular binding within the gill, thereby supporting a range of physiological processes in this organ. While beneficial at normal levels, these metals can become toxic when present in excess. Conversely, nonessential metals like cadmium (Cd) and lead (Pb) can gain entry into gill cells through similar metal transport pathways, potentially interfering with various cellular processes. The transepithelial transport of these metals across the gill epithelium is governed by a variety of metal transport and metal binding proteins. These include the Cu transporter 1 (CTR1), divalent metal transporter 1 (DMT1), and members of the Zrt-/Irt-like protein (ZIP) and zinc transport (ZnT) families. Additionally, some of these metals can compete with major ions (e.g., calcium, sodium) for absorption sites in the gill. This complex crosstalk suggests an interdependent mechanism that balances metal uptake to meet physiological needs while preventing excessive accumulation. In this article, I review the roles of trace metals in proteins/enzymes that support the different functions in the gill of teleost fish. I also discuss current understanding of the pathways involved in regulating the branchial uptake of metals and their influence on ionic regulation, and the potential detoxification mechanisms in the gill. Finally, I summarize knowledge gaps and potential areas for further investigation.

Ferroptosis is a new form of regulated necrosis characterized by iron-dependent lipid peroxidation, leading to irreparable lipid damage, membrane permeabilization, and necrotic cell death. Ferroptosis has recently been implicated in the pathogenesis of multiple forms of heart disease such as myocardial infarction, cardiac hypertrophy, heart failure, and various cardiomyopathies. Important progress has also been made regarding how ferroptosis is regulated in vitro and in vivo as well as its role in cardiac homeostasis and disease pathogenesis. In this review, we discuss molecular mechanisms that regulates ferroptosis in the heart, including pathways leading to iron overload and lipid peroxidation as well as the roles of key organelles in this process. We also discuss recent findings pertaining to the new pathogenic role of ferroptosis in various forms of heart disease as well as genetic and pharmacologic strategies targeting ferroptosis in the heart.

Iron is a critical transition metal required to sustain a healthy central nervous system. Iron is involved in metabolic reactions, enzymatic activity, myelinogenesis, and oxygen transport. However, in several pathological conditions such as cancer, neurodegeneration, and neurotrauma iron becomes elevated. Excessive iron can have deleterious effects leading to reactive oxygen species (ROS) via the Fenton reaction. Iron-derived ROS are known to drive several mechanisms such as cell death pathways including ferroptosis, necroptosis, and pyroptosis. Excessive iron present in the post-traumatic brain could trigger these harmful pathways potentiating the high rates of morbidity and mortality. In the present review, we will discuss how iron plays an intricate role in initiating ferroptosis, necroptosis, and pyroptosis, examine their potential link to traumatic brain injury morbidity and mortality, and suggest therapeutic targets.

The accidental human pathogen Legionella pneumophila (Lp) is the etiological agent for a severe atypical pneumonia known as Legionnaires' disease. In human infections and animal models of disease alveolar macrophages are the primary cellular niche that supports bacterial replication within a unique intracellular membrane-bound organelle. The Dot/Icm apparatus-a type IV secretion system that translocates ~300 bacterial proteins within the cytosol of the infected cell-is a central virulence factor required for intracellular growth. Mutant strains lacking functional Dot/Icm apparatus are transported to and degraded within the lysosomes of infected macrophages. The early foundational work from Dr. Horwitz's group unequivocally established that Legionella does not replicate extracellularly during infection-a phenomenon well supported by experimental evidence for four decades. Our data challenges this paradigm by demonstrating that macrophages and monocytes provide the necessary nutrients and support robust Legionella extracellular replication. We show that the previously reported lack of Lp extracellular replication is not a bacteria intrinsic feature but rather a result of robust restriction by serum-derived nutritional immunity factors. Specifically, the host iron-sequestering protein Transferrin is identified here as a critical suppressor of Lp extracellular replication in an iron-dependent manner. In iron-overload conditions or in the absence of Transferrin, Lp bypasses growth restriction by IFNγ-primed macrophages though extracellular replication. It is well established that certain risk factors associated with development of Legionnaires' disease, such as smoking, produce a chronic pulmonary environment of iron-overload. Our work indicates that iron-overload could be an important determinant of severe infection by allowing Lp to overcome nutritional immunity and replicate extracellularly, which in turn would circumvent intracellular cell intrinsic host defenses. Thus, we provide evidence for nutritional immunity as a key underappreciated host defense mechanism in Legionella pathogenesis.

Magnetic nanoparticles offer many exciting possibilities in biomedicine, from cell imaging to cancer treatment. One of the currently researched nanoparticles are magnetosomes, magnetite nanoparticles of high chemical purity synthesized by magnetotactic bacteria. Despite their therapeutic potential, very little is known about their degradation in human cells, and even less so of their degradation within tumours. In an effort to explore the potential of magnetosomes for cancer treatment, we have explored their degradation process in a 3D human lung carcinoma model at the subcellular level and with nanometre scale resolution. We have used state of the art hard X-ray probes (nano-XANES and nano-XRF), which allow for identification of distinct iron phases in each region of the cell. Our results reveal the progression of magnetite oxidation to maghemite within magnetosomes, and the biosynthesis of magnetite and ferrihydrite by ferritin.

Hemochromatosis is an inherited iron overload condition caused by mutations that reduce the levels of the iron-regulatory hormone hepcidin or its binding to ferroportin. The hepcidin-ferroportin axis is pivotal to iron homeostasis, providing opportunities for therapeutic intervention in iron overload disorders like hemochromatosis. The aim of this study was to evaluate the efficacy of the oral ferroportin inhibitor vamifeport in the Hfe C282Y mouse model, which carries the most common mutation found in patients with hemochromatosis. A single oral dose of vamifeport lowered serum iron levels in Hfe C282Y mice, with delayed onset and shorter duration than observed in wild-type mice. Vamifeport induced transient hypoferremia by inhibiting ferroportin and resulted in a feedback regulation of liver Hamp in wild-type mice, which was absent in Hfe C282Y mice, reflecting the dysregulated systemic iron sensing in this hemochromatosis model. Chronic dosing with vamifeport led to sustained serum and liver iron reductions in Hfe C282Y mice, as well as markedly reducing liver Hamp expression in Hfe C282Y mice, suggesting distinct regulation of liver Hamp expression following acute or continuous iron restriction via vamifeport. At the tested dose, vamifeport retained its activity when combined with phlebotomy and did not significantly interfere with liver iron removal by phlebotomy in Hfe C282Y mice. These data demonstrate that chronic vamifeport treatment significantly reduces serum iron levels and prevents liver iron loading in the Hfe C282Y mouse model of hemochromatosis, thus providing preclinical proof of concept for the efficacy of vamifeport in hemochromatosis with or without phlebotomy.

Transcriptional mechanisms establish and maintain complex genetic and protein networks to control cell state transitions. The hematopoietic transcription factor GATA1 is a master regulator of erythropoiesis and megakaryopoiesis, and human GATA1 genetic variants cause anemia and megakaryoblastic leukemia. Multiomic analyses revealed that GATA1 controls expression of transporters and metabolic enzymes that dictate intracellular levels of endogenous small molecules, including heme, metal ions, and sphingolipids. Besides its canonical function as a hemoglobin component, heme facilitates or antagonizes GATA1 function to regulate erythropoiesis via mechanisms dependent or independent of the heme-binding transcription factor BTB domain and CNC homology 1 (BACH1). GATA1 regulates the expression of genes encoding heme biosynthetic enzymes and BACH1. GATA1 maintains homeostasis of bioactive ceramides during erythroid differentiation by regulating genes encoding sphingolipid metabolic enzymes. Disrupting ceramide homeostasis impairs critical cytokine signaling and is detrimental to erythroid cells. During erythroid maturation, GATA1 induces a zinc transporter switch that favors export versus import, thus dictating the intracellular zinc level, erythroblast survival, and differentiation. In aggregate, these studies support an emerging paradigm in which GATA factor-dependent transcriptional mechanisms control the intracellular levels of endogenous small molecules and small molecule-dependent feedback loops that serve as vital effectors of transcription factor activity, genome function, and cell state transitions.

Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantia nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3' untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the SLC7A11-ALOX12 pathway, which was independent of GPX4. This study revealed that IRP2 homeostasis in the SN was critical for PD progression and clarified the molecular mechanism of ferroptosis caused by IRP2.

Iron and copper chelation therapy plays a crucial role in treating conditions associated with metal overload, such as hemochromatosis or Wilson's disease. However, conventional chelators face challenges in reaching the core of iron and copper metabolism - the mitochondria. Mitochondria-targeted chelators can specifically target and remove metal ions from mitochondria, showing promise in treating diseases linked to mitochondrial dysfunction, including neurodegenerative diseases and cancer. Additionally, they serve as specific mitochondrial metal sensors. However, designing these new molecules presents its own set of challenges. Depending on the chelator's intended use to prevent or to promote redox cycling of the metals, the chelating moiety must possess different donor atoms and an optimal value of the electrode potential of the chelator-metal complex. Various targeting moieties can be employed for selective delivery into the mitochondria. This review also provides an overview of the current progress in the design of mitochondria-targeted chelators and their biological activity investigation.

Atherosclerosis, characterized by the accumulation of plaque within the arterial walls, is an intricate cardiovascular disease that often results in severe health issues. Recent studies have emphasized the importance of ferroptosis, a controlled type of cell death dependent on iron, as a critical factor in this disease state. Ferroptosis, distinguished by its reliance on iron and the accumulation of lipid hydroperoxides, offers a unique insight into the pathology of atherosclerotic lesions. This summary encapsulates the current knowledge of the intricate role ferroptosis plays in the onset and progression of atherosclerosis. It explores the molecular processes through which lipid peroxidation and iron metabolism contribute to the development of atheromatous plaques and evaluates the possibility of utilizing ferroptosis as a novel treatment approach for atherosclerosis. By illuminating the intricate relationship between ferroptosis-related processes and atherosclerosis, this review paves the way for future clinical applications and personalized medicine approaches aimed at alleviating the effects of atherosclerosis.

Ferroptosis, spurred by excess labile iron and lipid peroxidation, is implicated in various diseases. Advances have been made in comprehending the lipid-peroxidation side of ferroptosis, but the exact role of iron in driving ferroptosis remains unknown. Although iron overload is characterized in multiple disease states, the potential role of ferroptosis within them remains undefined. This overview focuses on the 'ferro' side of ferroptosis, highlighting iron dysregulation in human diseases and potential therapeutic strategies targeting iron regulation and metabolism.

Iron is an important trace element that affects the growth and development of animals and regulates oxygen transport, hematopoiesis, and hypoxia adaptations. Wujin pig has unique hypoxic adaptability and iron homeostasis; however, the specific regulatory mechanisms have rarely been reported. This study randomly divided 18 healthy Wujin piglets into three groups: the control group, supplemented with 100 mg/kg iron (as iron glycinate); the low-iron group, no iron supplementation; and the high-iron group, supplemented with 200 mg/kg iron (as iron glycinate). The pre-feeding period was 5 days, and the formal period was 30 days. Serum was collected from empty stomachs before slaughter and at slaughter to detect changes in the serum iron metabolism parameters. Gene expression in the liver was analyzed via transcriptome analysis to determine the effects of low- and high-iron diets on transcriptome levels. Correlation analysis was performed for apparent serum parameters, and transcriptome sequencing was performed using weighted gene co-expression network analysis to reveal the key pathways underlying hypoxia regulation and iron metabolism. The main results are as follows. (1) Except for the hypoxia-inducible factor 1 (HIF-1) content (between the low- and high-iron groups), significant differences were not observed among the serum iron metabolic parameters. The serum HIF-1 content of the low-iron group was significantly higher than that of the high-iron group (p < 0.05). (2) Sequencing analysis of the liver transcriptome revealed 155 differentially expressed genes (DEGs) between the low-iron and control groups, 229 DEGs between the high-iron and control groups, and 279 DEGs between the low- and high-iron groups. Bioinformatics analysis showed that the HIF-1 and transforming growth factor-beta (TGF-β) signaling pathways were the key pathways for hypoxia regulation and iron metabolism. Four genes were selected for qPCR validation, and the results were consistent with the transcriptome sequencing data. In summary, the serum iron metabolism parameter results showed that under the influence of low- and high-iron diets, Wujin piglets maintain a steady state of physiological and biochemical indices via complex metabolic regulation of the body, which reflects their stress resistance and adaptability. The transcriptome results revealed the effects of low-iron and high-iron diets on the gene expression level in the liver and showed that the HIF-1 and TGF-β signaling pathways were key for regulating hypoxia adaptability and iron metabolism homeostasis under low-iron and high-iron diets. Moreover, HIF-1α and HEPC were the key genes. The findings provide a theoretical foundation for exploring the regulatory pathways and characteristics of iron metabolism in Wujin pigs.

Iron is an important cofactor for many proteins and is used to create Fe-S clusters and heme prosthetic groups that enzymes use to catalyze enzymatic reactions. Proteins involved in the import, export, and sequestration of iron are regulated by Iron Regulatory Proteins (IRPs). Recently, a patient with bi-allelic loss of function mutations in IREB2 leading to the absence of IRP2 protein was discovered. The patient failed to achieve developmental milestones and was diagnosed with dystonic cerebral palsy, epilepsy, microcytic hypochromic anemia, and frontal lobe atrophy. Several more IREB2 deficient patients subsequently identified manifested similar neurological problems. To better understand the manifestations of this novel neurological disease, we subjected an Irp2-null mouse model to extensive behavioral testing. Irp2-null mice had a significant motor deficit demonstrated by reduced performance on rotarod and hanging wire tests. Somatosensory function was also compromised in hot and cold plate assays. Their spatial search strategy was impaired in the Barnes maze and they exhibited a difficulty in flexibly adapting their response in the operant touchscreen reversal learning task. The latter is a cognitive behavior known to require an intact prefrontal cortex. These results suggest that loss of Irp2 in mice causes motor and behavioral deficits that faithfully reflect the IREB2 patient's neurodegenerative disorder.

In the small intestine, nutrients from ingested food are absorbed and broken down by enterocytes, which constitute over 95% of the intestinal epithelium. Enterocytes demonstrate diet- and segment-dependent metabolic flexibility, enabling them to take up large amounts of glutamine and glucose to meet their energy needs and transfer these nutrients into the bloodstream. During glycolysis, ATP, lactate, and H+ ions are produced within the enterocytes. Based on extensive but incomplete glutamine oxidation large amounts of alanine or lactate are produced. Lactate, in turn, promotes hypoxia-inducible factor-1α (Hif-1α) activation and Hif-1α-dependent transcription of various proton channels and exchangers, which extrude cytoplasmic H+-ions into the intestinal lumen. In parallel, the vitamin C-dependent and duodenal cytochrome b-mediated conversion of ferric iron into ferrous iron progresses. Finally, the generated electrochemical gradient is utilized by the divalent metal transporter 1 for H+-coupled uptake of non-heme Fe2+-ions. Iron efflux from enterocytes, subsequent binding to the plasma protein transferrin, and systemic distribution supply a wide range of cells with iron, including erythroid precursors essential for erythropoiesis. In this review, we discuss the impact of vitamin C on the redox capacity of human erythrocytes and connect enterocyte function with iron metabolism, highlighting its effects on erythropoiesis.

Transition metal ions are critically important across all kingdoms of life. The chemical properties of iron, copper, zinc, manganese, cobalt, and nickel make them very attractive for use as cofactors in metalloenzymes and/or metalloproteins. Their versatile chemistry in aqueous solution enables them to function both as electron donors and acceptors, and thus participate in both reduction and oxidation reactions respectively. Transition metal ions can also function as nonredox multidentate coordination sites that play essential roles in macromolecular structure and function. Malfunction in transition metal transport and homeostasis has been linked to a wide number of human diseases including cancer, diabetes, and neurodegenerative disorders. Transition metal transporters are central players in the physiology of transition metals whereby they move transition metals in and out of cellular compartments. In this review, we provide a comprehensive overview of in vitro reconstitution of the activity of integral membrane transition metal transporters and discuss strategies that have been successfully implemented to overcome the challenges. We also discuss recent advances in our understanding of transition metal transport mechanisms and the techniques that are currently used to decipher the molecular basis of transport activities of these proteins. Deep mechanistic insights into transition metal transport systems will be essential to understand their malfunction in human diseases and target them for potential therapeutic strategies.

SLC40A1 is the sole iron export protein reported in mammals. In humans, its dysfunction is responsible for ferroportin disease, an inborn error of iron metabolism transmitted as an autosomal dominant trait and observed in different ethnic groups. As a member of the major facilitator superfamily, SLC40A1 requires a series of conformational changes to enable iron translocation across the plasma membrane. The influence of lipids on protein stability and its conformational changes has been little investigated to date. Here, we combine molecular dynamics simulations of SLC40A1 embedded in membrane bilayers with experimental alanine scanning mutagenesis to analyze the specific role of glycerophospholipids. We identify four basic residues (Lys90, Arg365, Lys366, and Arg371) that are located at the membrane-cytosol interface and consistently interact with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) molecules. These residues surround a network of salt bridges and hydrogens bonds that play a critical role in stabilizing SLC40A1 in its basal outward-facing conformation. More deeply embedded in the plasma membrane, we identify Arg179 as a charged amino acid residue also tightly interacting with lipid polar heads. This results in a local deformation of the lipid bilayer. Interestingly, Arg179 is adjacent to Arg178, which forms a functionally important salt-bridge with Asp473 and is a recurrently associated with ferroportin disease when mutated to glutamine. We demonstrate that the two p.Arg178Gln and p.Arg179Thr missense variants have similar functional behaviors. These observations provide insights into the role of phospholipids in the formation/disruption of the SLC40A1 inner gate, and give a better understanding of the diversity of molecular mechanisms of ferroportin disease.

Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction secondary to infection, and the severity can range from mild delirium to deep coma. Disorders of iron metabolism have been proven to play an important role in a variety of neurodegenerative diseases by inducing cell damage through iron accumulation in glial cells and neurons. Recent studies have found that iron accumulation is also a potential mechanism of SAE. Systemic inflammation can induce changes in the expression of transporters and receptors on cells, especially high expression of divalent metal transporter1 (DMT1) and low expression of ferroportin (Fpn) 1, which leads to iron accumulation in cells. Excessive free Fe2+ can participate in the Fenton reaction to produce reactive oxygen species (ROS) to directly damage cells or induce ferroptosis. As a result, it may be of great help to improve SAE by treatment of targeting disorders of iron metabolism. Therefore, it is important to review the current research progress on the mechanism of SAE based on iron metabolism disorders. In addition, we also briefly describe the current status of SAE and iron metabolism disorders and emphasize the therapeutic prospect of targeting iron accumulation as a treatment for SAE, especially iron chelator. Moreover, drug delivery and side effects can be improved with the development of nanotechnology. This work suggests that treating SAE based on disorders of iron metabolism will be a thriving field.