Intracellular Iron Research Articles

Oxygen Vacancy-Rich Manganese Nanoflowers as Ferroptosis Inducers for Tumor Radiotherapy.

The combination of ferroptosis and innovative tumor therapy methods offers another promising answer to the problem of tumors. In order to generate effective ferroptosis in tumor cells, iron-based nanomaterials are commonly utilized to introduce foreign iron as a trigger for ferroptosis. However, this usually necessitates the injection of larger doses of iron into the body. These exogenous iron increases are likely to create concealed concerns for symptoms such as liver damage and allergy. Herein, an iron-free radiosensitizer is introduced, oxygen-vacancy-rich MnO2 nanoflowers (ovs-MnO2), that promotes ferroptosis and modifies the tumor microenvironment to assist radiotherapy. ovs-MnO2 with enriched oxygen vacancies on the surface induces the release of intracellular free iron (Fe2+), which functions as an activator of Fenton reaction and enhances the accumulation of intracellular reactive oxygen species. On the other hand, Fe2+ also triggers the ferroptosis and promotes the accumulation of lipid peroxides. Subsequently, the depletion of glutathione and accumulation of lipid peroxidation in tumor cells leads to the inactivation of glutathione peroxidase 4 (GPX4) and ferroptosis, thereby enhancing the therapeutic efficacy of radiotherapy. The nanoplatform provides a novel strategy for generating novel nanomedicines for ferroptosis-assisted radiotherapy.

SLC40A1 in iron metabolism, ferroptosis, and disease: A review.

Solute carrier family 40 member 1 (SLC40A1) plays an essential role in transporting iron from intracellular to extracellular environments. When SLC40A1 expression is abnormal, cellular iron metabolism becomes dysregulated, resulting in an overload of intracellular iron, which induces cell ferroptosis. Numerous studies have confirmed that ferroptosis is closely associated with the development of many diseases. Here, we review recent findings on SLC40A1 in ferroptosis and its association with various diseases, intending to explore new directions for research on disease pathogenesis and new therapeutic targets for prevention and treatment. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Metabolic Diseases > Molecular and Cellular Physiology.

Cr(VI) induces ferroptosis in DF-1 cells by simultaneously perturbing iron homeostasis of ferritinophagy and mitophagy

Hexavalent chromium [Cr(VI)] is an environmental pollutant known for its strong oxidizing and carcinogenic effects. However, its potential to induce ferroptosis in poultry remains poorly understood. This study aims to investigate the induction of ferroptosis by Cr(VI) in DF-1 cells and elucidate the underlying mechanisms. DF-1 cells exposed to Cr(VI) showed increased lipid reactive oxygen species and changes in ferroptosis marker genes (decreased expression of GPX4 and increased expression of COX2). Notably, the addition of the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) can reverse this effect. During the cell death process, Cr(VI) induced ferritinophagy, disrupting iron homeostasis and releasing labile iron ions. We predicted by docking that these iron ions would bind to mitochondrial membrane proteins through virtual docking. This binding was validated through colocalization analysis. In addition, Cr(VI) caused mitophagy, which releases additional ferrous ions. Therefore, Cr(VI) can induce the simultaneous release of ferrous ions through these pathways, thereby exacerbating lipid peroxidation and ultimately triggering ferroptosis in DF-1 cells. This study demonstrates that Cr(VI) can induce ferroptosis in DF-1 cells by disrupting intracellular iron homeostasis and providing valuable insights into the toxic effects of Cr(VI) in poultry and potentially other organisms.

CoQ10 targeted hippocampal ferroptosis in a status epilepticus rat model

Status epilepticus (SE), the most severe form of epilepsy, leads to brain damage. Uncertainty persists about the mechanisms that lead to the pathophysiology of epilepsy and the death of neurons. Overloading of intracellular iron ions has recently been identified as the cause of a newly recognized form of controlled cell death called ferroptosis. Inhibiting ferroptosis has shown promise as a treatment for epilepsy, according to recent studies. So, the current study aimed to assess the possible antiepileptic impact of CoQ10 either alone or with the standard antiepileptic drug sodium valproate (SVP) and to evaluate the targeted effect of COQ10 on hippocampal oxidative stress and ferroptosis in a SE rat model. Using a lithium-pilocarpine rat model of epilepsy, we evaluated the effect of SVP, CoQ10, or both on seizure severity, histological, and immunohistochemical of the hippocampus. Furthermore, due to the essential role of oxidative stress and lipid peroxidation in inducing ferroptosis, we evaluated malonaldehyde (MDA), reduced glutathione (GSH), glutathione peroxidase 4 (GPX4), and ferritin in tissue homogenate. Our work illustrated that ferroptosis occurs in murine models of lithium-pilocarpine-induced seizures (epileptic group). Nissl staining revealed significant neurodegeneration. A significant increase in the number of astrocytes stained with an astrocyte-specific marker was observed in the hippocampus. Effective seizure relief can be achieved in the seizure model by administering CoQ10 alone compared to SVP. This was accomplished by lowering ferritin levels and increasing GPX4, reducing MDA, and increasing GSH in the hippocampus tissue homogenate. In addition, the benefits of SVP therapy for regulating iron stores, GPX4, and oxidative stress markers were amplified by incorporating CoQ10 as compared to SVP alone. It was concluded that CoQ10 alone has a more beneficial effect than SVP alone in restoring histological structures and has a targeted effect on hippocampal oxidative stress and ferroptosis. In addition, COQ10 could be useful as an adjuvant to SVP in protecting against oxidative damage and ferroptosis-related damage that result from epileptic seizures.

Ferritin heavy chain supports stability and function of the regulatory T cell lineage

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten–eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

Capsaicin Enhances Temozolomide-Resistant Glioblastoma Cells’ Chemosensitivity and Ferroptosis through FHOD1/IRF2 Downregulation

Resistance of tumor cells to chemotherapy, particularly in the case of glioblastoma (GBM), a common brain tumor, presents a substantial challenge in oncology. In this study, we investigated the potential of capsaicin to overcome drug resistance in temozolomide (TMZ)-resistant U87 and U251 cells by targeting ferroptosis-mediated interferon regulatory factor (IRF)-2 and formin homology-2 domain-containing protein-1 (FHOD1) signal pathways. First, we induced TMZ resistance in these cells by treating them with TMZ for three weeks. Subsequently, we assessed the impacts of capsaicin on various aspects, including cell viability, proliferation, ferroptosis markers, levels of IRF2 and FHOD1, intracellular iron concentrations, and cell migration in these cells. Our results indicate that capsaicin treatment resulted in a significant decrease in both cell viability and proliferation in TMZ-resistant U87-R and U251-R cells. In addition, it effectively suppressed cell migration rates in these cells, targeting TMZ resistance. Furthermore, capsaicin demonstrated its ability to downregulate FHOD1, IRF2, glutathione, and glutathione peroxidase 4 levels in TMZ-resistant cells. This was accompanied by an increase in intracellular iron, total oxidant status, and increased malondialdehyde levels. Significantly, the treatment with capsaicin led to a notable decrease in the expressions of FHOD1 and IRF2 at both the mRNA and protein levels in U87-R and U251-R cells. In summary, our results emphasize the substantial potential of capsaicin in enhancing the sensitivity of TMZ-resistant GBM cells to chemotherapy. This effect is achieved through its modulation of ferroptosis-related pathways, involving the regulation of FHOD1 and IRF2 expressions.

Nanodrug Hijacking Blood Transferrin for Ferroptosis-Mediated Cancer Treatment.

Ferroptosis as a promising method of cancer treatment heavily relies on the intracellular iron ion level. Herein, a new iron-supplement nanodrug was developed by conjugating transferrin-homing peptide T10 on the surface of cross-linked lipoic acid vesicles (T10@cLAV), which could hijack blood transferrin (Tf) and specifically deliver it to tumor cells to elevate the Fe2+ level. Meanwhile, the intracellular degradation product of cLAV, dihydrolipoic acid, could regenerate Fe2+ to further boost the ferroptosis. The results disclosed that T10@cLAV achieved tumor inhibition comparable to that of cisplatin at a dose as low as 5 mg/kg in the HeLa tumor-bearing nude mice model and caused no toxicity at the dose up to 300 mg/kg. This tactful iron-supplement strategy of hijacking blood Tf is superior to the current strategies: one is the induction of intracellular ferritin degradation, which is limited by the low content of ferritin, and the other is the delivery of iron-based materials, which easily causes adverse effects.

Super-enhancer mediated upregulation of MYEOV suppresses ferroptosis in lung adenocarcinoma

Super-enhancers (SEs) exerted a crucial role in regulating the transcription of oncogenes across various malignancies while the roles of SEs driven genes and the core regulatory elements remain elusive in LUAD. In this study, cancer-specific-SE-genes of lung adenocarcinoma (LUAD) were profiled through H3K27ac ChIP-seq data of cancer cell lines and normal lung tissues, which enriched in in biological processes and pathways integral to the pathophysiology of LUAD. Based on this study, LUAD cells were susceptible to SEs inhibitors, with a reduction of cell proliferation as well as an elevation of apoptosis upon JQ1 or THZ1 intervention. Moreover, the integration of SEs landscapes, CRISPRi, ChIP-PCR, Hi-C data analysis and dual-luciferase reporter assays revealed that myeloma overexpressed gene (MYEOV) was aberrantly overexpressed in LUAD via transcriptional activation by the core SE elements. Functionally, the knockdown of MYEOV undermined cell proliferation in vitro and tumor growth in vivo. In addition, the knockdown of MYEOV generated a prominent ferroptotic phenotype, characterized by elevation of intracellular ferrous iron, reactive oxygen species and lipid peroxidation, together with alteration in marker proteins (SLC7A11, GPX4, FTH1, and ACSL4). Instead, the overexpression of MYEOV accelerated cell proliferation and abrogated ferroptosis. Clinically, the overexpression of MYEOV was observed in LUAD tissues indicating a poor prognosis in patients with LUAD. Mechanistically, SMPD1-induced autophagic degradation of GPX4 assumed a crucial role in the process of ferroptosis triggered by MYEOV knockdown. Serving as an oncogene repressing ferroptosis, promoting proliferation as well as shortening survival in LUAD, SEs-mediated activation of MYEOV might distinguish as a promising therapeutic target.

Beyond Mortality: Exploring the Influence of Plant Phenolics on Modulating Ferroptosis-A Systematic Review.

Ferroptosis is a recently discovered type of programmed cell death that is mechanistically different from other types of programmed cell death such as apoptosis, necroptosis, and autophagy. It is characterized by the accumulation of intracellular iron, overproduction of reactive oxygen species, depletion of glutathione, and extensive lipid peroxidation of lipids in the cell membrane. It was discovered that ferroptosis is interconnected with many diseases, such as neurodegenerative diseases, ischemia/reperfusion injury, cancer, and chronic kidney disease. Polyphenols, plant secondary metabolites known for many bioactivities, are being extensively researched in the context of their influence on ferroptosis which resulted in a great number of publications showing the need for a systematic review. In this review, an extensive literature search was performed. Databases (Scopus, Web of Science, PubMed, ScienceDirect, Springer) were searched in the time span from 2017 to November 2023, using the keyword "ferroptosis" alone and in combination with "flavonoid", "phenolic acid", "stilbene", "coumarin", "anthraquinone", and "chalcone"; after the selection of studies, we had 311 papers and 143 phenolic compounds. In total, 53 compounds showed the ability to induce ferroptosis, and 110 compounds were able to inhibit ferroptosis, and out of those compounds, 20 showed both abilities depending on the model system. The most researched compounds are shikonin, curcumin, quercetin, resveratrol, and baicalin. The most common modes of action are in the modulation of the Nrf2/GPX4 and Nrf2/HO-1 axis and the modulation of iron metabolism.

Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag.

Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.

Iron–sulfur cluster assembly scaffold protein IscU is required for activation of ferric uptake regulator (Fur) in Escherichiacoli

It was previously postulated that when intracellular free iron content is elevated in bacteria, the Ferric uptake regulator (Fur) binds its co-repressor a mononuclear ferrous iron to regulate intracellular iron homeostasis. However, the proposed iron-bound Fur had not been identified in any bacteria. In previous studies, we have demonstrated that Escherichia coli Fur binds a [2Fe-2S] cluster in response to elevation of intracellular free iron content, and that binding of the [2Fe-2S] cluster turns on Fur as an active repressor to bind a specific DNA sequence known as the Fur-box. Here we find that the iron-sulfur cluster assembly scaffold protein IscU is required for the [2Fe-2S] cluster assembly in Fur, as deletion of IscU inhibits the [2Fe-2S] cluster assembly in Fur and prevents activation of Fur as a repressor in E. coli cells in response to elevation of intracellular free iron content. Additional studies reveal that IscU promotes the [2Fe-2S] cluster assembly in apo-form Fur and restores its Fur-box binding activity in vitro. While IscU is also required for the [2Fe-2S] cluster assembly in the Haemophilus influenzae Fur in E. coli cells, deletion of IscU does not significantly affect the [2Fe-2S] cluster assembly in the E. coli ferredoxin and siderophore-reductase FhuF. Our results suggest that IscU may have a unique role for the [2Fe-2S] cluster assembly in Fur, and that regulation of intracellular iron homeostasis is closely coupled with iron-sulfur cluster biogenesis in E. coli.

Curcumin activates the JNK signaling pathway to promote ferroptosis in colon cancer cells.

Recent evidence has proved that curcumin as a natural polyphenol have a great anticancer and anti-proliferative effects in cancer cells. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. In this study, we aimed to examine the effects of curcumin in ferroptosis of human colorectal cancer cells and its underlying molecular mechanisms. SW-480 colorectal cancer cells were treated by curcumin with different concentrations. Cell viability was determined by using MTT assay. The concentrations of reactive oxygen species (ROS) and intracellular iron were measured using specific related kits. Real-time PCR and Western blot analysis were used to determine the expression of ferroptosis-related proteins including ACSL4, GPx4 and FTH1 and activation of JNK protein. Curcumin suppressed SW-480 cancer cells viability in dose-dependent manner. Cell treatment with curcumin led to accumulation of ROS and iron within cells and increase in the intracellular levels of lipid peroxidation. In addition, curcumin modulated the mRNA and protein expression levels of ferroptosis-related proteins including ACSL4, GPx4 and FTH1 and suppression of JNK signaling. Curcumin may exhibit its anticancer effect on colorectal cancer by downregulating JNK signaling to induce ferroptosis in SW-480 cells.

Mitochondrial ferritin alleviates ferroptosis in a kainic acid-induced mouse epilepsy model by regulating iron homeostasis: Involvement of nuclear factor erythroid 2-related factor 2.

Epilepsy is a widespread and chronic disease of the central nervous system caused by a variety of factors. Mitochondrial ferritin (FtMt) refers to ferritin located within the mitochondria that may protect neurons against oxidative stress by binding excess free iron ions in the cytoplasm. However, the potential role of FtMt in epilepsy remains unclear. We aimed to investigate whether FtMt and its related mechanisms can regulate epilepsy by modulating ferroptosis. Three weeks after injection of adeno-associated virus (AAV) in the skull of adult male C57BL/6 mice, kainic acid (KA) was injected into the hippocampus to induce seizures. Primary hippocampal neurons were transfected with siRNA using a glutamate-mediated epilepsy model. After specific treatments, Western blot analysis, immunofluorescence, EEG recording, transmission electron microscopy, iron staining, silver staining, and Nissl staining were performed. At different time points after KA injection, the expression of FtMt protein in the hippocampus of mice showed varying degrees of increase. Knockdown of the FtMt gene by AAV resulted in an increase in intracellular free iron levels and a decrease in the function of iron transport-related proteins, promoting neuronal ferroptosis and exacerbating epileptic brain activity in the hippocampus of seizure mice. Additionally, increasing the expression level of FtMt protein was achieved by AAV-mediated upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) gene in the hippocampus of seizure mice. In epilepsy, Nrf2 modulates ferroptosis by involving the expression of FtMt and may be a potential therapeutic mechanism of neuronal injury after epilepsy. Targeting this relevant process for treatment may be a therapeutic strategy to prevent epilepsy.

Enlightening the mechanism of ferroptosis in epileptic heart.

Epilepsy is a chronic neurological degenerative disease with a high incidence, affecting all age groups. Refractory Epilepsy (RE) occurs in approximately 30-40% of cases with a higher risk of sudden unexpected death in epilepsy (SUDEP). Recent studies have shown that spontaneous seizures developed in epilepsy can be related to an increase in oxidative stress and reactive oxygen derivatives (ROS) production. Increasing ROS concentration causes lipid peroxidation, protein oxidation, destruction of nuclear genetic material, enzyme inhibition, and cell death by a mechanism known as "ferroptosis" (Fts). Inactivation of glutathione peroxidase 4 (GPX4) induces Fts, while oxidative stress is linked with increased intracellular free iron (Fe+2) concentration. Fts is also a non-apoptotic programmed cell death mechanism, where a hypoxia-inducible factor 1 alpha (HIF-141) dependent hypoxic stress-like condition appears to occur with accumulation of iron and cytotoxic ROS in affected cells. Assuming convulsive crises as hypoxic stress, repetitive convulsive/hypoxic stress can be an effective inducer of the "epileptic heart" (EH), which is characterized by altered autonomic function and a high risk of malignant or fatal bradycardia. We previously reported that experimental recurrent seizures induce cardiomyocyte Fts associated with SUDEP. Furthermore, several genes related to Fts and hypoxia have recently been identified in acute myocardial infarction. An emerging theme from recent studies indicates that inhibition of GPX4 through modulating expression or activities of the xCT antiporter system (SLC7A11) governs cell sensitivity to oxidative stress from ferroptosis. Furthermore, during hypoxia, an increased expression of stress transcriptional factor ATF3 can promote Fts induced by erastin in a HIF-141-dependent manner. We propose that inhibition of Fts with ROS scavengers, iron chelators, antioxidants, and transaminase inhibitors could provide a therapeutic effect in epilepsy and improve the prognosis of SUDEP risk by protecting the heart from ferroptosis.

Ferritin: Significance in viral infections.

As an indispensable trace element, iron is essential for many biological processes. Increasing evidence has shown that virus infection can perturb iron metabolism and play a role in the occurrence and development of viral infection-related diseases. Ferritin plays a crucial role in maintaining the body's iron homoeostasis. It is an important protein to stabilise the iron balance in cells. Ferritin is a 24-mer hollow iron storage protein composed of two subunits: ferritin heavy chain and ferritin light chain. It was reported that ferritin is not only an intra-cellular iron storage protein, but also a pathogenic mediator that enhances the inflammatory process and stimulates the further inflammatory pathway, which is a key member of the vicious pathogenic cycle to perpetuate. Ferritin exerts immuno-suppressive and pro-inflammatory functions during viral infection. In this review, we describe in detail the basic information of ferritin in the first section, including its structural features, the regulation of ferritin. In the second part, we focus on the role of ferritin in viral infection-related diseases and the molecular mechanisms by which viral infection regulates ferritin. The last section briefly outlines the potential of ferritin in antiviral therapy. Given the importance of iron and viral infection, understanding the role of ferritin during viral infection helps us understand the relationship between iron metabolic dysfunction and viral infection, which provides a new direction for the development of antiviral therapeutic drugs.

Kinase PIM1 governs ferroptosis to reduce retinal microvascular endothelial cell dysfunction triggered by high glucose.

Previous studies have implicated targeting Pim-1 proto-oncogene, serine/threonine kinase (PIM1) as a preventive measure against high glucose-induced cellular stress and apoptosis. This study aimed to reveal the potential role and regulatory mechanism of PIM1 in diabetic retinopathy. Human retinal microvascular endothelial cells (hRMECs) underwent high glucose induction, and fluctuations in PIM1 levels were assessed. By overexpressing PIM1, its effects on the levels of inflammatory factors, oxidative stress indicators, migration and tube formation abilities, tight junction protein expression levels, and ferroptosis in hRMECs were identified. Afterwards, hRMECs were treated with the ferroptosis-inducing agent erastin, and the effect of erastin on the above PIM1 regulatory functions was focused on. PIM1 was downregulated upon high glucose, and its overexpression inhibited the inflammatory response, oxidative stress, cell migration, and tube formation potential in hRMECs, whereas elevated tight junction protein levels. Furthermore, PIM1 overexpression reduced intracellular iron ion levels, lipid peroxidation, and levels of proteins actively involved in ferroptosis. Erastin treatment reversed the impacts of PIM1 on hRMECs, suggesting the mediation of ferroptosis in PIM1 regulation. The current study has yielded critical insights into the role of PIM1 in ameliorating high glucose-induced hRMEC dysfunction through the inhibition of ferroptosis.

Dihydroartemisinin (DHA) inhibits myofibroblast differentiation through inducing ferroptosis mediated by ferritinophagy

Idiopathic pulmonary fibrosis (IPF) is caused by persistent micro-injuries and aberrant repair processes. Myofibroblast differentiation in lung is a key event for abnormal repair. Dihydroartemisinin(DHA), a well-known anti-malarial drug, have been shown to alleviate pulmonary fibrosis, but its mechanism is not clear. Ferroptosis is involved in the pathgenesis of many diseases, including IPF. Ferritinophagy is a form of cellular autophagy which regulates intracellular iron homeostasis. The function of DHA on myofibroblasts differentiation of pulmonary and whether related with ferroptosis and ferritinophagy are unknown now. Using human fetal lung fibroblast 1(HFL1) cell line and the qRT-PCR, immunofluorescent and Western blotting techniques, we found that after TGF-β1 treatment, the levels of ɑ-SMA expression and ROS increased; the mRNA and protein levels of FTH1 and NCOA4, the content of Fe2+ and 4-HNE increased significantly at 6h, then gradually reduced with time. After DHA treatment, FHL1 cells appeared ferroptosis; the levels of α-SMA mRNA and protein reduced and the levels of ROS and 4-HNE increased; the Fe2+ levels decreased sharply at 6h, then increased with time, and were higher than normal since 24h; the mRNA and protein levels of FTH1 and NCOA4 decreased, exhibited a downward trend. These results show that Fe2+, ROS and lipid peroxidation are involved in and ferritinophagy is inhibited during fibroblast-to-myofibroblast differentiation; The depletion of Fe2+ at early stage induced by DHA treatment triggers the ferritinophagy in HFL1 cells, leading to degradation of FTH1 and NCOA4 and following increase of Fe2+ levels. DHA may inhibit the fibroblast-to-myofibroblast differentiation through inducing ferroptosis mediated by ferritinophagy.

Ferroptosis in viral infection: a potential therapeutic target.

Ferroptosis, known as a type of programmed cell death that is iron dependent, is characterized by intracellular iron accumulation, glutathione depletion, glutathione peroxidase inactivationand lipid peroxidation. More and more research in recent years has demonstrated the tight connection between viral infections and ferroptosis. This article reviews the potential role and mechanism of ferroptosis in viral infection, and these findings will help in the prevention and treatment of the virus.

A novel fluorescent probe for visualizing viscosity changes in lipid droplets during chemotherapy-induced ferroptosis

BackgroundFerroptosis, as a novel form of cell death, is becoming one of the hot topics in cancer treatment research. It differs from necrosis and autophagy in that it involves the accumulation of lipid peroxides and is triggered by iron dependency. Recent studies have suggested that this mechanism may alter the viscosity or structure of lipid droplets (LDs). The relationship between LDs viscosity and ferroptosis remains an active area of research with limited reports at present. Additionally, there is a lack of effective anticancer drugs targeting the ferroptosis pathway to promote ferroptosis in tumour cells. Therefore, the development of tools to detect viscosity changes during ferroptosis and targeted therapeutic strategies is of great significance. ResultsBy coupling 1,3-indandione with naphthalimide, including decamethylamine as a LDs recognition group, we designed and synthesized an environmental fluorescent probe that induces intramolecular charge transfer (TICT) effects. Notably, the diffusion and transport of intracellular substances may be affected in highly viscous environments. Under such conditions, intracellular iron ions may accumulate, leading to peroxide production and cellular damage, which can trigger ferroptosis. Therefore, WD-1 achieved excellent in situ bioimaging of LDs targeting and its viscosity during ferroptosis in HeLa cells and zebrafish. Furthermore, it was observed that WD-1 effectively differentiated between malignant and normal cells during this process, highlighting its potential significance in distinguishing cellular states. In addition, we used the antitumour drug paclitaxel to study ferroptosis in cancer cells. These findings not only provide an excellent tool for the development of the ferroptosis response, but also are crucial for understanding the biological properties of LDs during the ferroptosis response. Significance and noveltyBased on a powerful tool of fluorescent probe with in vivo bioimaging, we developed WD-1 to track the impact of paclitaxel on the process of ferroptosis in living cells. Therefore, we preliminarily believe that paclitaxel may affect the occurrence of ferroptosis and control apoptosis in cancer cells. These findings not only serve as an exceptional tool for advancing our understanding of the ferroptosis response, but furthermore play a vital role in comprehending the biological characteristics of LDs in relation to ferroptosis.

Hemochromatosis: Ferroptosis, ROS, Gut Microbiome, and Clinical Challenges with Alcohol as Confounding Variable.

Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.