Regulator Of Iron Homeostasis Research Articles

Multiple myeloma (MM) is a malignant disease characterized by the clonal proliferation of plasma cells in the bone marrow. Currently incurable, relapse and drug resistance remain significant challenges, necessitating the exploration of novel anti-MM agents. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical player in MM pathology and treatment. With advancing research, emerging evidence links ferroptosis to MM pathogenesis and therapeutic strategies. Natural products (NPs) and certain antitumor agents, owing to their broad bioactivities, demonstrate unique pharmacological advantages in MM therapy by targeting ferroptosis-related pathways. This review systematically examines ferroptosis-related pathways in MM pathogenesis, focusing on pharmacological and toxicological mechanisms of natural products (NPs) and antitumor compounds in modulating ferroptosis-related pathways. It aims to provide novel insights and strategies for MM research and clinical therapy. We systematically retrieved data from PubMed, Web of Science, ScienceDirect, SciFinder, Scopus, and the China National Knowledge Infrastructure (CNKI) spanning database inception to March 2025, followed by taxonomic integrative analysis of NPs' and antitumor compounds' echanistic classifications. NPs and antitumor compounds exert anti-MM effects via ferroptosis modulation, mechanistically mediated through: 1) lipid metabolism reprogramming; 2) ferritinophagy-driven iron homeostasis regulation; 3) Reactive oxygen species (ROS)-mediated oxidative stress potentiation; 4) autophagic activation; 5) Genes and proteins regulation. NPs and antitumor compounds demonstrate therapeutic potential against MM through multi-dimensional ferroptosis modulation, yet clinical translation faces two critical hurdles: 1) predominant focus on single-target mechanisms lacking systems pharmacology-level network analysis; 2) overreliance on in vitro models with insufficient clinical validation. Prioritize developing biomarkers and ferroptosis inducers to advance novel ferroptosis-targeting anticancer compounds.

SummaryPolyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines function as endogenous buffers of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using genome-wide CRISPR screens, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, GPX4. Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.

Bloodstream bacterial infections cause one-third of deaths from bacterial infections, and eradication of circulating bacteria is essential to prevent disseminated infections. Here, we found that hepcidin, the master regulator of systemic iron homeostasis, affected Kupffer cell (KC) immune defense against bloodstream bacterial infections by modulating the gut commensal bacteria–derived tryptophan derivative indole-3-propionic acid (IPA). Hepcidin deficiency impaired bacterial capture by KCs and exacerbated systemic bacterial dissemination through morphological changes in KCs. Gut microbiota depletion and fecal microbiota transplantation revealed that the gut microbiota mediated the alteration of KCs volume. Mechanistically, hepcidin deficiency led to a decreased abundance of the IPA-producing commensal Lactobacillus intestinalis and a concomitant reduction in the gut-to-liver shuttling of its metabolite IPA. IPA supplementation or L. intestinalis colonization restored the KC volume and hepatic immune defense against bloodstream bacterial infection in hepcidin-deficient mice. Moreover, hepcidin levels in patients with bacteremia were associated with days of antibiotic usage and hospitalization. Collectively, our findings highlight a previously unappreciated role of hepcidin in sustaining KC-mediated hepatic defense against bloodstream bacterial infections through the gut commensal L. intestinalis and its tryptophan derivative IPA. More importantly, we show that restoring the crosstalk between the gut microbiota and liver through IPA-inspired therapies may offer a promising strategy for enhancing the host defense against bloodstream bacterial infections in those with low hepcidin levels and a high risk for bacterial infections.

Small Molecule Regulation of Iron Homeostasis: Design and Optimization of Novel Iron Chelators Based on a Thiosemicarbazone Scaffold.

Background: Iron is an important micronutrient under physiological conditions, including pregnancy. On the other hand, excessive iron intake is also associated with adverse pregnancy outcomes. Macrophages are crucial in regulating iron homeostasis and pregnancy conditions. However, the role of macrophages in iron metabolism during pregnancy is unclear. Therefore, we used mouse models to investigate whether maternal iron overload induces pregnancy complications and their interactions with macrophages. Methods and Results: Administration of high-dose iron (iron dextran) by intraperitoneal injection to pregnant mice induced pregnancy complications such as fetal death, but low-dose iron did not affect fetal weight. In the placenta, the amount of iron was significantly increased and levels of macrophages were decreased by iron administration. In the liver, iron administration dramatically increased the amount of iron, with increased inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-6. Macrophages were observed to surround deposited iron in the liver. In an in vitro experiment, treatment with iron stimulated TNFα secretion with cell death in macrophages, but not in liver cells. To investigate the importance of macrophages during pregnancy, clodronate liposomes were administered to reduce macrophages in pregnant mice. The macrophage reduction in pregnant mice resulted in an increased absorption rate and fetal growth restriction, together with higher iron accumulation and inflammatory cytokines in the liver. Conclusions: Maternal excess iron may induce inflammatory conditions with macrophage dysfunction in the liver, resulting in pregnancy complications. The reduction in macrophages also induced higher iron levels and adverse effects during pregnancy, suggesting a vicious cycle between excessive iron and macrophage dysfunction during pregnancy.

Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, is implicated in various diseases, but effective therapeutic strategies remain limited. Lysosomal impairments cause iron dysregulation and initiate ferroptosis, which potentially contribute to ionizing radiation‐induced tissue damages. Here, the role of intercellular lysosomal regulation in governing iron homeostasis and protecting against ferroptosis is investigated in models of stem cell aggregation and mandibular regeneration post‐irradiation. Lysosomes are discovered to accumulate in specific regions within multi‐stem cell aggregates and regulate cell aggregate formation based on iron control, which is occurred through hypoxic signaling‐driven lysosomal redistribution mediated by extracellular vesicles. These vesicles exhibit lysosomal features and possess iron‐regulating properties, which rescue lysosomal defects to restore iron homeostasis and mitigate ferroptosis in recipient endothelial cells against the irradiation challenge. Based on lysosomal regulation and anti‐ferroptosis, these cell aggregate‐released extracellular vesicles (CA‐EVs) stimulate the growth of CD31+endomucin+ specialized vessels despite irradiation both in vitro and in vivo, which further promote bone regeneration of post‐irradiation mandibular defect. These findings highlight the potential of taking CA‐EVs as natural therapeutic agents to safeguard lysosomal function, modulate iron metabolism, and protect against ferroptosis, paving an avenue for combating post‐irradiation endothelial injuries and enhancing tissue regeneration.

The process of ferritinophagy, which involves the selective autophagic breakdown of ferritin triggered by nuclear receptor coactivator 4 (NCOA4), has been shown to regulate ferroptosis. Recent studies have confirmed that ferritinophagy plays a key role in the formation and progression of cardiovascular diseases. The mechanism of ferritinophagy involves the phagocytosis of ferritin by NCOA4, which binds ferritin and delivers it to the autophagosome. There, it fuses with lysosomes to degrade ferritin and release iron. This process is not only involved in iron-dependent responses, but also in the progression of a variety of human diseases, including metabolism-related diseases, neurodegenerative diseases, cardiovascular diseases, and infectious diseases. In cardiovascular diseases, ferritinophagy plays a central role in inducing ferroptosis, a mode of programmed cell death caused by lipid peroxidation. This process is regulated by intracellular iron homeostasis and reactive oxygen species production. It has been demonstrated that ferritinophagy promotes ferroptosis by increasing intracellular iron content. Furthermore, the influence of ferritinophagy in cardiovascular diseases has been further demonstrated. For instance, ischemia-reperfusion injury, atherosclerosis, myocardial disease and heart failure are all associated with ferritin levels. The early detection of ferritin levels, maintenance of iron homeostasis, prevention of iron overload and exploration of the interrelationship between ferritinophagy and cardiac diseases can provide new ideas for the prevention and treatment of cardiovascular diseases. Therapeutic options for ferritinophagy are also being explored. For instance, the inhibition of O-GlcNAcylation modification has been shown to promote ferritinophagy, which releases iron stored in ferritin and further regulates ferroptosis. Ferritinophagy has been demonstrated to play an important role in the formation and progression of cardiovascular diseases, influencing disease development by regulating iron homeostasis and ferroptosis. Future studies may further reveal the specific mechanisms and develop new therapeutic strategies.

Introduction and Objective: To investigate the role of the NCOA4-FTH1 axis in regulating iron metabolism, ferroptosis, and fibrosis in diabetic kidney disease (DKD) and explore its potential as a therapeutic target. Methods: We utilized db/db mice and renal cells cultured under high-glucose and high-fat conditions to establish in vivo and in vitro DKD models. Oxidative stress, ferrous iron, lipid peroxidation, iron metabolism genes, and fibrosis markers were evaluated using biochemical assays, immunofluorescence, and Western blotting. The effects of NCOA4 knockdown, FTH1 deficiency, and treatment with HIF-1 inhibitors (YC-1) or metformin were assessed on ferroptosis and fibrosis. Results: Renal tissues from DKD mice and DKD cell model exhibited iron overload, especially ferrous iron, along with elevated lipid peroxidation and mitochondrial changes indicative of ferroptosis, and dysregulated NCOA4 and FTH1 expression. Knocking down FTH1 promoted ferroptosis and fibrosis, while NCOA4 knockdown under high glucose and lipid conditions restored FTH1 levels, inhibiting ferroptosis and fibrosis. Elevated NCOA4 in DKD mice correlated with HIF-1αexpression, and in vitro hypoxia increased HIF-1α and NCOA4. Treatment with YC-1 or metformin reduced HIF-1α and NCOA4 expression, attenuating intracellular lipid peroxidation and ferroptosis in renal tubular cells. Conclusion: This study identifies the NCOA4-FTH1 axis as a critical regulator of iron metabolism and ferroptosis in DKD. Targeting this pathway can mitigate oxidative stress and fibrosis, providing a novel therapeutic strategy for DKD. Disclosure X. Chen: None. M. Zhang: None. Funding National Natural Science Foundation of China (82370828); the Improvement of Clinical Ability Project of Jiangsu Province Hospital (JSPH-MA-2021-3)

TolC, a multifunctional outer membrane protein, creates a continuous conduit that extrudes substrates from the bacterial periplasm and the outer leaflet of the inner membrane to the external environment. TolC of Vibrio species functions as an outer membrane protein of multiple exporters, and is involved in antibiotic efflux, regulation and export of virulence factors, iron homeostasis, and survival under various extreme environments, thereby playing an indispensable role in the pathogenesis of Vibrio species. This review recapitulates the current knowledge about the functions and regulators of TolC homologous proteins in Vibrio species.

Tiliroside induces ferroptosis and suppresses tumor growth by synergistically targeting AKR1B1 and modulating iron metabolism in ovarian cancer cells.

Ferroptosis, a regulated form of cell death marked by iron-dependent lipid peroxidation, has gained recognition as a potential therapeutic target in diverse cancers, including gastrointestinal stromal tumors (GIST). The NCOA4-mediated ferritinophagy pathway is integral to the regulation of cellular iron homeostasis and the process of ferroptosis. Nevertheless, the effects of modulating this pathway on the viability of GIST cells and the induction of ferroptosis are yet to be elucidated. This study sought to examine the impact of toosendanin (TSN), a natural compound with prospective anticancer attributes, on ferroptosis in GIST cells, specifically emphasizing its regulatory influence on the NCOA4-mediated ferritinophagy pathway. GIST-T1 cells were exposed to different concentrations of TSN. Cell viability, apoptosis, and ferroptosis were evaluated through flow cytometry (Annexin V/7-AAD), transmission electron microscopy (TEM), and biochemical detection. The proliferation, migration, and invasion capacities were assessed utilizing the Cell Counting Kit-8 (CCK-8) assay, clone formation assay, and Transwell assay, respectively. The impact of NCOA4 silencing and ferrostatin-1, an inhibitor of ferroptosis, was analyzed in conjunction with TSN treatment. The results showed that TSN treatment markedly decreased cell viability and induced ferroptosis in GIST-T1 cells, as demonstrated by elevated levels of lipid reactive oxygen species (ROS), increased ferrous ion content, and membrane damage. Mechanistically, western blot analysis demonstrated that TSN downregulated the expression of key ferroptosis inhibitors glutathione peroxidase 4 (GPX4) and SLC7A11, while simultaneously upregulating NCOA4 and LC3II/I. The application of small interfering RNA (siRNA)-NCOA4 and ferrostatin-1, which inhibit NCOA4-mediated autophagy and ferroptosis, resulted in a significant restoration of GPX4 and SLC7A11 expression, thereby mitigating TSN-induced ferroptosis. Furthermore, TSN was found to effectively suppress the proliferation, migration, and invasion of GIST cells; these effects were reversed upon NCOA4 silencing and inhibition of ferroptosis. This study underscores the potential of TSN as a therapeutic agent for GIST, particularly through the exploitation of NCOA4-mediated ferritinophagy to induce ferroptosis.

Dual role of hepcidin in response to pathogens.

FTO facilitates colorectal cancer chemoresistance via regulation of NUPR1-dependent iron homeostasis.

Candida albicans is an important pathogenic fungus that can cause superficial to life-threatening infections. Iron is essential for almost all organisms, yet it is highly restricted within the human host to defend against pathogens. To grow and survive in the iron-limited host environment, C. albicans has evolved multiple iron acquisition mechanisms. Understanding the regulation of iron homeostasis is, therefore, critical for elucidating C. albicans pathogenesis and virulence. This study explores the novel functions of C. albicans Rap1, with a focus on its contribution to iron acquisition and utilization. Our findings further highlight how iron availability impacts antifungal resistance and virulence through Rap1, providing insight into the complex iron regulatory machinery of C. albicans.

Hepcidin is a key regulator of systemic iron homeostasis, which is essential for maintaining iron balance and cellular health. To investigate its role in zebrafish, we empolyed a hepcidin knockout model. Morphological and histological analyses revealed pale livers and significant iron accumulation in hep−/− zebrafish, particularly in liver, skin, and egg tissues. RNA sequencing identified 1,424 differentially expressed genes (DEGs) between wild-type (WT) and hep−/− zebrafish, with significant enrichment in pathways related to ferroptosis, fatty acid degradation, and heme binding. Western blot analysis showed reduced levels of key iron-related proteins, including GPX4, Fth1, and ferroportin (FPN), indicating impaired iron transport and increased oxidative stress. Gene Ontology (GO) and KEGG analyses highlighted disruptions in iron metabolism and lipid oxidation, linking iron overload to ferroptosis in the absence of hepcidin. These findings demonstrate that hepcidin deficiency leads to profound dysregulation of iron homeostasis, driving lipid peroxidation and ferroptosis in the zebrafish liver. Our study provides mechanistic insights into the molecular consequences of hepcidin loss, advancing our understanding of iron-related oxidative damage and its physiological impacts.

Anemia is a common and multifactorial condition, often resulting from iron deficiency, chronic disease, or genetic disorders. One key regulator of iron homeostasis is hepcidin, a liver-produced hormone that plays a pivotal role in iron metabolism. Elevated or dysregulated hepcidin levels can lead to iron-restricted anemia, while reduced hepcidin expression can contribute to iron overload conditions. This review aims to explore the role of hepcidin in anemia and its potential as a target for precision medicine. We discuss the molecular mechanisms underlying hepcidin regulation, its interaction with iron transporters like ferroportin, and the clinical implications of hepcidin dysfunction in various types of anemia. Moreover, we examine the emerging therapeutic approaches aimed at modulating hepcidin expression or activity to treat iron-related disorders. Understanding the intricate regulation of hepcidin offers exciting prospects for precision-based therapies in anemia management, with potential applications in both iron-deficiency anemia and anemia of chronic disease. Keywords: Hepcidin, Anemia, Iron metabolism, Precision medicine, Iron deficiency, Chronic disease anemia, Ferroportin

Although erythropoiesis-stimulating agents (ESAs) have improved anemia management, some patients on maintenance hemodialysis (HD) exhibit hyporesponsiveness. Hepcidin, a key regulator of iron homeostasis, may play a role in this process. However, its potential as a marker for ESA hyporesponsiveness remains unclear due to conflicting findings of previous studies. This study aimed to evaluate serum hepcidin-25 as a marker for ESA hyporesponsiveness and identify factors influencing hepcidin levels in HD patients. This prospective observational study included 478 HD patients receiving ESA from the INFINITY cohort. Blood samples were collected before and after ESA administration to measure serum hepcidin-25. ESA hyporesponsiveness was defined by an erythropoietin resistance index (ERI) of 15 or higher. Logistic regression and linear regression analyses were used to identify factors associated with ESA hyporesponsiveness and hepcidin levels. Among patients receiving ESAs, 15% were classified as hyporesponsive. In the darbepoetin alpha group, hyporesponsive patients had lower hepcidin-25 levels; however, this association was not retained in multivariable analysis. No difference in hepcidin was observed in the recombinant human erythropoietin (EPO) group. Higher C-reactive protein (CRP), ferritin, transferrin saturation (TSAT), albumin, and glycoalbumin were linked to increased hepcidin, while being male and higher ESA dosage were associated with lower hepcidin levels. Hepcidin-25 levels were lower in ESA hyporesponsive patients; however, the association was not significant in multivariable analysis. Thus, routine measurement of hepcidin may not be necessary for diagnosing ESA hyporesponsiveness. The novel association between hepcidin and glycoalbumin suggests an interaction between iron regulation and glucose metabolism, warranting further study.

Iron responsive element (IREs) mRNA and iron regulatory proteins (IRPs) regulate iron homeostasis. 5'-untranslated region motifs of APP IREs fold into RNA stem loops bind to IRP to control translation. Through the 5'-UTR APP IREs, iron overload accelerated the translation of the Alzheimer's amyloid precursor protein (APP). The protein synthesis activator eIF4F and the protein synthesis repressor IRP1 are the two types of proteins that IREs bind. Iron regulates the competitive binding of eIF4F and IRP1 to IRE. Iron causes the IRE and eIF4F to associate with one other, causing the dissociation of IRPs and altered translation. In order to control IRE-modulated expression of APP, messenger RNAs are becoming attractive targets for the development of small molecule therapeutics. Many mRNA interference strategies target the 2-D RNA structure, but messenger RNAs like rRNAs and tRNAs can fold into complicated, three-dimensional structures that add another level of complexity. IREs family is one of the few known 3-D mRNA regulatory elements. In this review, I present IREs structural and functional characteristics. For iron metabolism, the mRNAs encoding the proteins are controlled by this family of similar base sequences. Iron has a similar way of controlling the expression of Alzheimer's APP as ferritin IRE RNA in their 5ÚTR. Further, iron mis regulation by IRPs can be investigated and contrasted using measurements of expression levels of APP, amyloid-β and tau formation. Accordingly, IRE-modulated APP expression in Alzheimer's disease has great therapeutic potential through targeting mRNA structures.

Iron is required for redox homeostasis but poses toxicity risks due to its redox activity. Erythropoiesis hence requires tight regulation of iron utilization for hemoglobin synthesis. The requirement for iron in erythropoiesis has necessitated the evolution of mechanisms to handle the iron required for hemoglobinization. FAM210B was identified as a regulator of mitochondrial iron import and heme synthesis in erythroid cell culture and zebrafish models. Here, we demonstrate that while FAM210B is required for erythroid differentiation and heme synthesis under standard cell culture conditions, holotransferrin supplementation was sufficient to chemically complement the iron-deficient phenotype. To investigate the role of FAM210B in erythropoiesis, we used knockout mice. While Fam210b−/− mice were viable and did not exhibit overt erythropoietic defects in the bone marrow, the male mice exhibited an increase in serum transferrin suggesting sex-specific alterations in systemic iron sensing. Upon phlebotomy- induced stress erythropoiesis, Fam210b−/− mice exhibited differences in serum transferrin levels, and more starkly, had markedly smaller spleens indicating defects in stress response. Fam210b−/− males had defects in neutrophil and monocyte numbers, as well as decreased erythroid progenitor numbers during erythropoietic stress. Together, our findings show that Fam210b plays a key role in splenic response to erythropoietic stress Our findings reveal a critical role for FAM210B in mediating splenic stress erythropoiesis and suggest it may act as a sex-specific regulator potentially linked to androgen signaling.

Iron is essential for vital biological processes, with its metabolism closely linked to host-pathogen interactions. Pseudomonas donghuensis HYS, with its superior iron uptake capacity, demonstrates pronounced virulence toward Caenorhabditis elegans. However, the virulence mechanisms remain unexplored. Ferric uptake regulator (Fur) regulates iron homeostasis and pathogenicity in bacteria, yet its role in HYS-mediated C. elegans pathogenesis requires systematic investigation. In this study, comparing the pathogenic processes of HYS and P. aeruginosa PA14 revealed that HYS causes stronger, irreversible toxicity via distinct mechanisms. Transcriptomics revealed that HYS infection disrupts C. elegans iron metabolism pathways, specifically iron transport, and iron-sulfur cluster utilization. Fur was identified as a pivotal regulator in HYS virulence and was indispensable for its colonization. Specifically, Fur was critical for disrupting nematode iron metabolism, as fur deletion eliminated this effect. While Fur regulated two HYS siderophores, neither of them mediated in the iron metabolism disruption of C. elegans. Screening identified Fur-regulated virulence factors to further investigate the function of Fur in HYS virulence, particularly alkaline proteases, and type II secretion system components. This study highlight that HYS can disrupt the iron metabolism pathway in C. elegans; Fur serves as a pivotal positive regulator in HYS-induced damage, particularly in disrupting iron metabolism through a siderophore-independent pathway. These findings expand the understanding of Pseudomonas pathogenicity and Fur-mediated virulence regulation.