Iron Metabolism Research Articles

Ferroptosis: a promising target for fumarate hydratase-deficient tumor therapeutics literature review.

This review aims to investigate the ferroptosis mechanism of fumarate hydratase (FH)-related tumors for the purpose of possible treatment of tumors. Ferroptosis is an iron (Fe)-dependent form of regulated cell death caused by lipid peroxidation on the cell membrane. Studies have implicated FH in tumorigenesis. As mutations in the FH gene alter cellular metabolism and increase tumorigenesis risk, particularly in the kidneys. As most tumor cells require higher amounts of ferrous ions (Fe2+) than normal cells, they are more susceptible to ferroptosis. Recent studies have indicated that ferroptosis is inhibited the pathogenesis and progression of FH-deficient tumors by regulating lipid and iron metabolism, glutathione-glutathione peroxidase 4 (GSH-GPX4), nuclear factor-erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathways. While the Fe2+ content is significantly lower in FH-deficient tumor cells, than that in normal cells. It is promising to promote ferroptosis by increasing the concentration of Fe2+ in cells to achieve the purpose of tumor treatment. In this study, we searched for relevant articles on ferroptosis and FH-deficient tumors using PubMed database. FH is a tumor suppressor. A number of basic studies have shown that the loss of FH plays an important role in hereditary leiomyomas and tumors such as renal cell carcinoma, ovarian cancer, and other tumors. This type of tumor cells can through induce ferroptosis, inhibit proliferation, migration and invasion of tumor cells, increase the sensitivity of tumor cells to chemotherapy, and reverse the drug resistance through various molecular mechanisms. At present, the research on ferroptosis in FH-related tumors is still in the basic experimental stage. This article reviews the anti-tumor effects and mechanisms of FH and ferroptosis, in order to further explore the medical value of ferroptosis in FH-related tumor therapy.

Diagnostic value and method of soluble transferrin receptor for suspected coronary artery disease: a case-control study.

Many studies have pointed out that iron overload in the body is a risk factor for coronary atherosclerosis (AS), while there are also studies that show that iron deficiency is associated with coronary AS. There is still no consensus on how iron metabolism affects coronary artery disease (CAD). This study aimed to analyze the relationship between iron metabolism indexes and CAD, investigate the diagnostic value of soluble transferrin receptor (sTfR) in suspected CAD, and establish a diagnostic model. This was a retrospective study. A total of 268 people with CAD-like symptoms who underwent coronary angiography in the Department of Cardiovascular Medicine, The Second Affiliated Hospital of Anhui Medical University from September 2022 to May 2023 without other chronic diseases or related medication history were included in the study and formed a continuous series including 188 CAD patients and 80 control subjects. Each iron metabolism index was divided into a grade variable according to tertile. The comparison of CAD morbidity between the tertiles and nonlinear correlation test was conducted to investigate the relationship between iron metabolism indexes and CAD risk. We used restricted cubic spline (RCS) to plot the relationship curve between sTfR and CAD risk and to determine the sTfR value corresponding to the minimal odds, according to which we divided the total sample into the "sTfR low level" subgroup and the "sTfR high level" subgroup. Logistic regression analyses were used to establish diagnostic models in both subgroups. The diagnostic efficiency of the indexes and models was compared by receiver operating characteristic (ROC) analysis. There is a "J" shape correlation between sTfR and CAD risk. Age/sTfR ratio [area under the curve (AUC) =0.690, 95% confidence interval (CI): 0.598-0.782, specificity 0.488 and sensitivity 0.842] has the best diagnostic efficiency in the "sTfR low level" subgroup. The diagnostic efficiency of sTfR (AUC =0.701, 95% CI: 0.598-0.803, specificity 0.541 and sensitivity 0.797) in the "sTfR high level" subgroup was higher than that of cardiac troponin I (cTnI) (AUC =0.674, 95% CI: 0.564-0.784, specificity 0.719 and sensitivity 0.653). The specific diagnostic methods were as follows: (I) When sTfR ≤1.087 mg/L, calculate the age/sTfR ratio, which indicates the diagnosis of CAD when the result is >58.595; (II) We can directly make a preliminary clinical diagnosis of CAD when sTfR >1.205 mg/L. Except for the above 2 cases, we can initially rule out a diagnosis of CAD. The iron metabolism index sTfR correlates with CAD morbidity in a "J" shape. With superior diagnostic efficacy than cTnI, sTfR can assist in diagnosing CAD in patients with CAD-like symptoms. In addition, sTfR can provide guidance for the management of body iron levels in CAD patients.

МАТЕМАТИЧЕСКОЕ МОДЕЛИРОВАНИЕ В ДИФФЕРЕНЦИАЛЬНОЙ ДИАГНОСТИКЕ АНЕМИИ ХРОНИЧЕСКИХ ЗАБОЛЕВАНИЙ И ЖЕЛЕЗОДЕФИЦИТНОЙ АНЕМИИ У ПАЦИЕНТОВ С ВОСПАЛИТЕЛЬНЫМИ ЗАБОЛЕВАНИЯМИ СУСТАВОВ

Aim. To develop based on the indicators of clinical blood tests, some biochemical markers, iron metabolism and cytokines a mathematical model that allows with high sensitivity and specificity to conduct differential diagnosis of anemia of chronic diseases (AHD) and iron deficiency anemia (IDA) in patients with inflammatory joint diseases (rheumatoid arthritis (RA), psoriatic arthritis (PSA), ankylosing spondylitis (AS)). Material and methods. The study included 104 patients with inflammatory joint diseases and anemic syndrome (37 males/67 females, age 48.4±5.42 years old), of which 54 patients with RA, 27 patients with PSA and 23 patients with AS. The control group consisted of 22 patients with inflammatory diseases of the joints without anemia (13 males/9 females, age 47.8±3.55 years old), of which 7 patients with RA, 10 with PSA, 5 with AS. For all patients, in addition to hemogram parameters, the concentrations of interleukin-6, interleukin-10, interleukin-1β, interferon-gamma, tumor necrosis factor alpha, ferritin, C-reactive protein, hepcidin, transferrin, soluble transferrin receptor were determined. For quantitative indicators, the median, standard error of the mean, and interquartile range was calculated. The significance of differences between several unrelated groups was determined using the Kruskal-Wallis test. The calculation of a mathematical model for the differential diagnosis of ACD and IDA was carried out using discriminant analysis. Results. As a result of the study, a canonical linear discriminant function (CLDF) was obtained: CLDF = 1.612171-0.002725× Hepcidin -0.005429× Ferritin The coordinates of the centroids are calculated, for ACD it is -1.44222008, and for IDA it is 1.52705656. A patient whose CLDF value is determined based on ferritin and hepcidin concentrations should be classified into the ACD or IDA group based on the minimum distance to the corresponding centroid. The resulting mathematical model has 100% sensitivity and 80% specificity. Conclusions. The equation based on hepcidin and ferritin (obtained from the results of discriminant analysis) allows, with high sensitivity, specificity and information ability, to carry out differential diagnosis of ACD and IDA in patients with inflammatory joints diseases instantly at the stage of initial contact with the doctor. Using of the equation will make it possible to more effectively diagnose and correct these types of anemia in this pathology, including for the purpose of more effective treatment.

Neuronal ferroptosis and ferroptosis-mediated endoplasmic reticulum stress: Implications in cognitive dysfunction induced by chronic intermittent hypoxia in mice

Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia–reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc − GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.

Redox-Regulated Iron Metabolism and Ferroptosis in Ovarian Cancer: Molecular Insights and Therapeutic Opportunities.

Ovarian cancer (OC), known for its lethality and resistance to chemotherapy, is closely associated with iron metabolism and ferroptosis-an iron-dependent cell death process, distinct from both autophagy and apoptosis. Emerging evidence suggests that dysregulation of iron metabolism could play a crucial role in OC by inducing an imbalance in the redox system, which leads to ferroptosis, offering a novel therapeutic approach. This review examines how disruptions in iron metabolism, which affect redox balance, impact OC progression, focusing on its essential cellular functions and potential as a therapeutic target. It highlights the molecular interplay, including the role of non-coding RNAs (ncRNAs), between iron metabolism and ferroptosis, and explores their interactions with key immune cells such as macrophages and T cells, as well as inflammation within the tumor microenvironment. The review also discusses how glycolysis-related iron metabolism influences ferroptosis via reactive oxygen species. Targeting these pathways, especially through agents that modulate iron metabolism and ferroptosis, presents promising therapeutic prospects. The review emphasizes the need for deeper insights into iron metabolism and ferroptosis within the redox-regulated system to enhance OC therapy and advocates for continued research into these mechanisms as potential strategies to combat OC.

Ribonuclease inhibitor 1 emerges as a potential biomarker and modulates inflammation and iron homeostasis in sepsis

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

Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis.

Aging is associated with a decline in the number and fitness of adult stem cells 1-4 . Aging-associated loss of stemness is posited to suppress tumorigenesis 5,6 , but this hypothesis has not been tested in vivo . Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells 7,8 , we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.

Characteristics of Gut Microbiota and Fecal Metabolites in Patients with Colorectal Cancer-Associated Iron Deficiency Anemia.

Patients with colorectal cancer (CRC) have a high prevalence of iron deficiency anemia (IDA), and the gut microbiota is closely related to iron metabolism. We performed metagenomic and metabolomic analyses of stool samples from 558 eligible samples, including IDA CRC patients (IDA, n = 69), non-anemia CRC patients (Non-Anemia, n = 245), and healthy controls (CTRL, n = 244), to explore the dynamically altered gut microbes and their metabolites. Compared with the CTRL group, fecal bacteria in both the IDA group and the Non-Anemia group showed a decrease in alpha diversity and changes in microbial communities. Flavonifractor plautii (F. plautii) increases progressively from CTRL to Non-Anemia to IDA, accompanied by decreased trimethoxyflavanone and a downregulated KO gene, megDIII. In the Non-Anemia group, Parabacteroides showed a specifically elevated abundance positively correlated with enriched 1,25-dihydroxyvitamin D3. The intricate correlations among gut microbiota, metabolites, and KO genes were uncovered and highlighted, implicating an aberrant iron metabolism vulnerable to chronic inflammation during the deterioration of the anemic condition. Furthermore, the amount of F. plautii in feces achieved independent and effective prediction performance for the poor outcome of CRC. Perturbed host-microbe interplays represent a novel prospect for explaining the pathogenesis of CRC-associated IDA. The fecal microbial features also reflect the associations between IDA and elevated CRC recurrence risk.

Abnormality in Peripheral and Brain Iron Contents and the Relationship with Grey Matter Volumes in Major Depressive Disorder.

Major depressive disorder (MDD) is a prevalent mental illness globally, yet its etiology remains largely elusive. Recent interest in the scientific community has focused on the correlation between the disruption of iron homeostasis and MDD. Prior studies have revealed anomalous levels of iron in both peripheral blood and the brain of MDD patients; however, these findings are not consistent. This study involved 95 MDD patients aged 18-35 and 66 sex- and age-matched healthy controls (HCs) who underwent 3D-T1 and quantitative susceptibility mapping (QSM) sequence scans to assess grey matter volume (GMV) and brain iron concentration, respectively. Plasma ferritin (pF) levels were measured in a subset of 49 MDD individuals and 41 HCs using the Enzyme-linked immunosorbent assay (ELISA), whose blood data were simultaneously collected. We hypothesize that morphological brain changes in MDD patients are related to abnormal regulation of iron levels in the brain and periphery. Multimodal canonical correlation analysis plus joint independent component analysis (MCCA+jICA) algorithm was mainly used to investigate the covariation patterns between the brain iron concentration and GMV. The results of "MCCA+jICA" showed that the QSM values in bilateral globus pallidus and caudate nucleus of MDD patients were lower than HCs. While in the bilateral thalamus and putamen, the QSM values in MDD patients were higher than in HCs. The GMV values of these brain regions showed a significant positive correlation with QSM. The GMV values of bilateral putamen were found to be increased in MDD patients compared with HCs. A small portion of the thalamus showed reduced GMV values in MDD patients compared to HCs. Furthermore, the region of interest (ROI)-based comparison results in the basal ganglia structures align with the outcomes obtained from the "MCCA+jICA" analysis. The ELISA results indicated that the levels of pF in MDD patients were higher than those in HCs. Correlation analysis revealed that the increase in pF was positively correlated with the iron content in the left thalamus. Finally, the covariation patterns obtained from "MCCA+jICA" analysis as classification features effectively differentiated MDD patients from HCs in the support vector machine (SVM) model. Our findings indicate that elevated peripheral ferritin in MDD patients may disrupt the normal metabolism of iron in the brain, leading to abnormal changes in brain iron levels and GMV.

The DNA damage response of Escherichia coli, revisited: Differential gene expression after replication inhibition

In 1967, in this journal, Evelyn Witkin proposed the existence of a coordinated DNA damage response in Escherichia coli, which later came to be called the "SOS response." We revisited this response using the replication inhibitor azidothymidine (AZT) and RNA-Seq analysis and identified several features. We confirm the induction of classic Save our ship (SOS) loci and identify several genes, including many of the pyrimidine pathway, that have not been previously demonstrated to be DNA damage-inducible. Despite a strong dependence on LexA, these genes lack LexA boxes and their regulation by LexA is likely to be indirect via unknown factors. We show that the transcription factor "stringent starvation protein" SspA is as important as LexA in the regulation of AZT-induced genes and that the genes activated by SspA change dramatically after AZT exposure. Our experiments identify additional LexA-independent DNA damage inducible genes, including 22 small RNA genes, some of which appear to activated by SspA. Motility and chemotaxis genes are strongly down-regulated by AZT, possibly as a result of one of more of the small RNAs or other transcription factors such as AppY and GadE, whose expression is elevated by AZT. Genes controlling the iron siderophore, enterobactin, and iron homeostasis are also strongly induced, independent of LexA. We confirm that IraD antiadaptor protein is induced independent of LexA and that a second antiadaptor, IraM is likewise strongly AZT-inducible, independent of LexA, suggesting that RpoS stabilization via these antiadaptor proteins is an integral part of replication stress tolerance.

Central Vein Sign and Paramagnetic Rim Lesions: Susceptibility Changes in Brain Tissues and Their Implications for the Study of Multiple Sclerosis Pathology.

Multiple sclerosis (MS) is the most common acquired inflammatory and demyelinating disease in adults. The conventional diagnostic of MS and the follow-up of inflammatory activity is based on the detection of hyperintense foci in T2 and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and lesions with brain-blood barrier (BBB) disruption in the central nervous system (CNS) parenchyma. However, T2/FLAIR hyperintense lesions are not specific to MS and the MS pathology and inflammatory processes go far beyond focal lesions and can be independent of BBB disruption. MRI techniques based on the magnetic susceptibility properties of the tissue, such as T2*, susceptibility-weighted images (SWI), and quantitative susceptibility mapping (QSM) offer tools for advanced MS diagnostic, follow-up, and the assessment of more detailed features of MS dynamic pathology. Susceptibility-weighted techniques are sensitive to the paramagnetic components of biological tissues, such as deoxyhemoglobin. This capability enables the visualization of brain parenchymal veins. Consequently, it presents an opportunity to identify veins within the core of multiple sclerosis (MS) lesions, thereby affirming their venocentric characteristics. This advancement significantly enhances the accuracy of the differential diagnostic process. Another important paramagnetic component in biological tissues is iron. In MS, the dynamic trafficking of iron between different cells, such as oligodendrocytes, astrocytes, and microglia, enables the study of different stages of demyelination and remyelination. Furthermore, the accumulation of iron in activated microglia serves as an indicator of latent inflammatory activity in chronic MS lesions, termed paramagnetic rim lesions (PRLs). PRLs have been correlated with disease progression and degenerative processes, underscoring their significance in MS pathology. This review will elucidate the underlying physical principles of magnetic susceptibility and their implications for the formation and interpretation of T2*, SWI, and QSM sequences. Additionally, it will explore their applications in multiple sclerosis (MS), particularly in detecting the central vein sign (CVS) and PRLs, and assessing iron metabolism. Furthermore, the review will discuss their role in advancing early and precise MS diagnosis and prognostic evaluation, as well as their utility in studying chronic active inflammation and degenerative processes.

Alpha-synuclein affects certain iron transporters of BV2 microglia cell through its ferric reductase activity.

Alpha-synuclein (α-syn) is a major component of Lewy bodies, which is a biomarker of Parkinson's disease (PD). It accumulates in substantia nigra pars compacta (SNpc) to form insoluble aggregates and cause neurotoxicity, which is often accompanied by iron deposition. We compared the iron reductase activity between monomeric α-syn (M-α-syn) and oligomeric α-syn (O-α-syn) and investigated the effect of α-syn on iron metabolism of BV2 microglia cells as well. α-syn had ferric reductase activity, and O-α-syn had stronger enzyme activity than M-α-syn. M-α-syn upregulated iron uptake protein, divalent metal transporter1 (DMT1) expression, and iron influx but did not regulate iron release protein ferroportin1 (FPN1) expression and iron efflux. O-α-syn elevated the expression of both DMT1 and FPN1 and thus increased the iron influx and efflux in BV2 microglial cells, but the expressions of iron regulatory protein1 (IRP1) and hypoxia-inducible factor 2α (HIF-2α) had no significant change. Moreover, both M-α-syn and O-α-syn could increase the mRNA expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in BV2 microglia cells. Both types of α-syn can activate microglia, which leads to increased expressions of proinflammatory factors. α-syn can affect DMT1 and FPN1 expressions in BV2 microglia cells, which might be through its ferric reductase activity.NEW & NOTEWORTHY The effects of monomeric α-syn (M-α-syn) and oligomeric α-syn (O-α-syn) on the iron metabolism of BV2 microglia cells were detected by exogenous α-syn treatment. This study provides a strong experimental basis for α-syn involvement in iron metabolism in microglia.

Do iron homeostasis biomarkers mediate the associations of liability to type 2 diabetes and glycemic traits in liver steatosis and cirrhosis: a two-step Mendelian randomization study

BackgroundPrevious studies, including Mendelian randomization (MR), have demonstrated type 2 diabetes (T2D) and glycemic traits are associated with increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). However, few studies have explored the underlying pathway, such as the role of iron homeostasis.MethodsWe used a two-step MR approach to investigate the associations of genetic liability to T2D, glycemic traits, iron biomarkers, and liver diseases. We analyzed summary statistics from various genome-wide association studies of T2D (n = 933,970), glycemic traits (n ≤ 209,605), iron biomarkers (n ≤ 246,139), MASLD (n ≤ 972,707), and related biomarkers (alanine aminotransferase (ALT) and proton density fat fraction (PDFF)). Our primary analysis was based on inverse-variance weighting, followed by several sensitivity analyses. We also conducted mediation analyses and explored the role of liver iron in post hoc analysis.ResultsGenetic liability to T2D and elevated fasting insulin (FI) likely increased risk of liver steatosis (ORliability to T2D: 1.14 per doubling in the prevalence, 95% CI: 1.10, 1.19; ORFI: 3.31 per log pmol/l, 95% CI: 1.92, 5.72) and related biomarkers. Liability to T2D also likely increased the risk of developing liver cirrhosis. Genetically elevated ferritin, serum iron, and liver iron were associated with higher risk of liver steatosis (ORferritin: 1.25 per SD, 95% CI 1.07, 1.46; ORliver iron: 1.15 per SD, 95% CI: 1.05, 1.26) and liver cirrhosis (ORserum iron: 1.31, 95% CI: 1.06, 1.63; ORliver iron: 1.34, 95% CI: 1.07, 1.68). Ferritin partially mediated the association between FI and liver steatosis (proportion mediated: 7%, 95% CI: 2–12%).ConclusionsOur study provides credible evidence on the causal role of T2D and elevated insulin in liver steatosis and cirrhosis risk and indicates ferritin may play a mediating role in this association.

Identification and differentiation of rice ferritin gene in two different chromosomes in several local Indonesian rice varieties

Abstract. Permatasari SE, Salamah A. 2024. Identification and differentiation of rice ferritin gene in two different chromosomes in several local Indonesian rice varieties. Biodiversitas 25: 2547-2555. The presence of ferritin protein in rice plants indicates a regulatory response to environmental iron stress. It prevents the destructive effects of the chain reaction resulting from Fe2+ accumulation in the cell. This study aimed to detect and identify the location of the ferritin gene (OsFER) in eight local rice varieties in Indonesia. OsFER2, as the target gene was amplified using PCR, visualized by electrophoresis, and then sequenced. The sequencing results were analyzed using DNA Baser, BioEdit, and ClustalX2. The predicted proteins were visualized using the SWISS-MODEL server, Rice Genome Annotation Project Database, and chromosome map tools. The results show that all rice varieties studied have 100% alignment similarity and OsFER characteristics on chromosome 11 at LOC_Os11g01530 and chromosome 12 at LOC_Os12g01530, which have striking differences. The complete protein structure of the complex is found on chromosome 12, while only a portion of alpha-helix ferritin is found on chromosome 11. Differences in the position of the ferritin gene at different chromosomes impact the functional changes in the ferritin protein as an iron homeostasis key role. The two genes show different characteristics and are located at different genomic positions, suggesting a potential regulatory impact on the level of iron stress resistance in Indonesian rice varieties.

The Urinary Glycopeptide Profile Differentiates Early Cardiorenal Risk in Subjects Not Meeting Criteria for Chronic Kidney Disease.

Early diagnosis and treatment of chronic kidney disease (CKD) is a worldwide challenge. Subjects with albumin-to-creatinine ratio (ACR) ≥ 30 mg/g and preserved renal function are considered to be at no cardiorenal risk in clinical practice, but prospective clinical studies evidence increased risk, even at the high-normal (HN) ACR range (10-30 mg/g), supporting the need to identify other molecular indicators for early assessment of patients at higher risk. Following our previous studies, here we aim to stratify the normoalbuminuria range according to cardiorenal risk and identify the glycoproteins and N-glycosylation sites associated with kidney damage in subclinical CKD. Glycoproteins were analyzed in urine from hypertensive patients within the HN ACR range compared to control group (C; ACR < 10 mg/g) by mass spectrometry. A different cohort was analyzed for confirmation (ELISA) and sex perspective was evaluated. Patients' follow-up for 8 years since basal urine collection revealed higher renal function decline and ACR progression for HN patients. Differential N-glycopeptides and their N -glycosylation sites were also identified, together with their pathogenicity. N-glycosylation may condition pathological protein deregulation, and a panel of 62 glycoproteins evidenced alteration in normoalbuminuric subjects within the HN range. Haptoglobin-related protein, haptoglobin, afamin, transferrin, and immunoglobulin heavy constant gamma 1 (IGHG1) and 2 (IGHG2) showed increased levels in HN patients, pointing to disturbed iron metabolism and tubular reabsorption and supporting the tubule as a target of interest in the early progression of CKD. When analyzed separately, haptoglobin, afamin, transferrin, and IGHG2 remained significant in HN, in both women and men. At the peptide level, 172 N-glycopeptides showed differential abundance in HN patients, and 26 showed high pathogenicity, 10 of them belonging to glycoproteins that do not show variation between HN and C groups. This study highlights the value of glycosylation in subjects not meeting KDIGO criteria for CKD. The identified N-glycopeptides and glycosylation sites showed novel targets, for both the early assessment of individual cardiorenal risk and for intervention aimed at anticipating CKD progression.

Mitochondrial GCN5L1 acts as a novel regulator for iron homeostasis to promote sorafenib sensitivity in hepatocellular carcinoma

BackgroundSorafenib resistance is becoming increasingly common and disadvantageous for hepatocellular carcinoma (HCC) treatment. Ferroptosis is an iron dependent programmed cell death underlying the mechanism of sorafenib. Iron is crucial for synthesis of cofactors essential to mitochondrial enzymes and necessary for HCC proliferation, while mitochondrial iron overload and oxidative stress are associated with sorafenib induced ferroptosis. However, the crosstalk among iron homeostasis and sorafenib resistance is unclear.MethodsWe conducted bioinformatics analysis of sorafenib treated HCC datasets to analyze GCN5L1 and iron related gene expression with sorafenib resistance. GCN5L1 deleted HCC cell lines were generated by CRISPR technology. Sorafenib resistant HCC cell line was established to validate dataset analysis and evaluate the effect of potential target.ResultsWe identified GCN5L1, a regulator of mitochondrial acetylation, as a modulator in sorafenib-induced ferroptosis via affecting mitochondrial iron homeostasis. GCN5L1 deficiency significantly increased sorafenib sensitivity in HCC cells by down-regulating mitochondrial iron transporters CISD1 expression to induce iron accumulation. Mitochondrial iron accumulation leads to an acceleration in cellular and lipid ROS. Sorafenib resistance is related to CISD1 overexpression to release mitochondrial iron and maintaining mitochondrial homeostasis. We combined CISD1 inhibitor NL-1 with sorafenib, which significantly enhanced sorafenib-induced ferroptosis by promoting mitochondrial iron accumulation and lipid peroxidation. The combination of NL-1 with sorafenib enhanced sorafenib efficacy in vitro and in vivo.ConclusionsOur findings demonstrate that GCN5L1/CISD1 axis is crucial for sorafenib resistance and would be a potential therapeutic strategy for sorafenib resistant HCC.

Inhaled polystyrene microplastics impaired lung function through pulmonary flora/TLR4-mediated iron homeostasis imbalance

Microplastics (MPs) have been found in the air, human nasal cavity, and lung, suggesting that the respiratory tract is one of the important exposure routes for MPs. The lung is a direct target organ for injury from inhaled MPs, but data on lung injury from longer-term exposure to environmental doses of MPs are limited, and the mechanisms remain unclear. Here, C57BL/6 J mice were treated with 5 μm polystyrene (PS)-MPs by intratracheal instillation (0.6, 3, and 15 mg/kg) for 60 days to establish MPs exposure model. We found that PS-MPs lead to increased collagen fibers and decreased lung barrier permeability and lung function in lung tissue. Mechanistically, the abundance of gram-negative bacteria in the pulmonary flora increased after inhalation of PS-MPs, causing lipopolysaccharide (LPS) release. The expression of Toll-like receptor 4 (TLR4), the key receptor of LPS, was increased, and ferroptosis occurred in lung tissue cells. Further in vitro intervention experiments were performed, pulmonary flora/TLR4-induced imbalance of lung iron homeostasis is an important mechanism of PS-MPs-induced lung injury. Our study provides new evidence for lung injury caused by environmental doses of MPs and strategies to prevent it through longer-term dynamic observation.

The involvement of IRP2-induced ferroptosis through the p53-SLC7A11-ALOX12 pathway in Parkinson's disease

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.

Meconium Proteins Involved in Iron Metabolism.

The lack of specific biological materials and biomarkers limits our knowledge of the mechanisms underlying intrauterine regulation of iron supply to the fetus. Determining the meconium content of proteins commonly used in the laboratory to assess the transport, storage, and distribution of iron in the body may elucidate their roles in fetal development. Ferritin, transferrin, haptoglobin, ceruloplasmin, lactoferrin, myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), and calprotectin were determined by ELISA in meconium samples obtained from 122 neonates. There were strong correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL (p < 0.05). Meconium concentrations of ferritin were several-fold higher than the concentrations of the other proteins, with the exception of calprotectin whose concentration was approximately three-fold higher than that of ferritin. Meconium ceruloplasmin concentration significantly correlated with the concentrations of MPO, NGAL, lactoferrin, and calprotectin. Correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL may reflect their collaborative involvement in the storage and transport of iron in the intrauterine environment in line with their recognized biological properties. High meconium concentrations of ferritin may provide information about the demand for iron and its utilization by the fetus. The associations between ceruloplasmin and neutrophil proteins may indicate the involvement of ceruloplasmin in the regulation of neutrophil activity in the intrauterine environment.

The Intersection of Hepcidin and Polycystic Ovary Syndrome: A Review of Current Understanding

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting up to 13% of reproductive-age women. It is characterized by a constellation of symptoms including menstrual irregularities, hyperandrogenism, and polycystic ovaries, often intertwined with metabolic disturbances such as insulin resistance and dyslipidemia. Hepcidin is a liver-produced peptide hormone that regulates iron homeostasis, with a significant role in the pathophysiology of PCOS. Hepcidin controls iron absorption and storage by binding to ferroportin, leading to its degradation and reducing iron export from enterocytes and macrophages. In PCOS patients, hepcidin dysregulation is linked to underlying hormonal and metabolic abnormalities, including insulin resistance and hyperandrogenism. Studies consistently demonstrate decreased hepcidin levels in PCOS patients, resulting in altered iron metabolism parameters, such as increased serum iron and ferritin concentrations, leading to iron overload. This iron overload can exacerbate complications like anemia. The relationship between hepcidin, anemia, and PCOS is influenced by several mechanisms. Hyperandrogenism in PCOS inhibits hepcidin synthesis, reducing iron sequestration and increasing serum iron levels, contributing to erythropoiesis and potentially mitigating anemia, while also posing a risk of iron overload. Hyperinsulinemia associated with insulin resistance further decreases hepcidin levels, enhancing dietary iron absorption and increasing serum iron levels. Despite the chronic low-grade inflammation typical in PCOS, which usually increases hepcidin levels, the inflammation may not be sufficient to override the suppressive effects of hyperandrogenism and hyperinsulinemia on hepcidin expression. Oligomenorrhea or amenorrhea in PCOS leads to reduced menstrual blood loss, contributing to iron retention and further influencing hepcidin regulation. Genetic and epigenetic factors also significantly impact hepcidin expression and iron metabolism in PCOS.