Iron Overload Research Articles

Emerging Therapeutic Approaches Targeting Ferroptosis in Cancer: Focus on Immunotherapy and Nanotechnology.

Ferroptosis is a newly discovered form of programmed cell death characterized by iron overload, ROS accumulation, and lipid peroxidation. It is distinguished by unique morphological, biochemical, and genetic features and stands apart from other known regulated cell death mechanisms. Studies have demonstrated a close association between ferroptosis and various cancers, including liver cancer, lung cancer, renal cell carcinoma, colorectal cancer, pancreatic cancer, and ovarian cancer. Inducing ferroptosis has shown promising results in inhibiting tumor growth and reversing tumor progression. However, the challenge lies in regulating ferroptosis in vivo due to the scarcity of potent compounds that can activate it. Integrating emerging biomedical discoveries and technological innovations with conventional therapies is imperative. Notably, considerable progress has been made in cancer treatment by leveraging immunotherapy and nanotechnology to trigger ferroptosis. This review explores the relationship between ferroptosis and emerging immunotherapies and nanotechnologies, along with their potential underlying mechanisms, offering valuable insights for developing novel cancer treatment strategies.

The role of iron(II) excess and phosphate to synthesize hydroxychloride green rust

Green rust (GR) is a chemically reactive mineral of interest for environmental remediation. However, the lack of stability of this compound is a major drawback for practical applications. In this study, the precipitation of hydroxychloride green rust type 1 (GR1Cl) from soluble FeII and FeIII species was studied by analyzing pH titration curves and employing XRD, Raman and Mössbauer spectroscopies to find optimal conditions for synthesizing GR1Cl. Using the stoichiometric condition for FeII-FeIII corresponding to the [FeII3FeIII(OH)8]Cl compound, FeIIIO(OH)2.9Cl0.1 was formed in a first step during the addition of NaOH and then transformed into a mixture of GR1Cl and Fe3O4. The addition of phosphate anions (PO4) at a molar ratio PO4: Fe = 1: 10 in the initial solution was shown to avoid the formation of undesired magnetite. Interestingly, GR1Cl was also the only product without adding PO4 using an excess of FeII species in solution, i.e. for an initial ferric molar fraction x = FeIII: Fetot of 0.2. First experimental evidences of a hydroxyphosphate green rust type 2 GR2PO4 were also provided by XRD and Raman spectroscopy. Therefore, this work may attract interest for a better understanding of the geochemical cycle of iron and phosphate in natural environments such as hydromorphic soils or hydrothermal chimneys where fougerite, the mineral homologue of synthetic GR, is supposed to play a significant role.

The role of TF-b in iron homeostasis and bacterial defense in common carp (Cyprinus carpio)

Transferrin (TF) is a prototypical biological macromolecule protein known for its iron-binding properties. TF proteins play a crucial role in modulating host iron homeostasis and defending against pathogen invasion. In this study, we utilized common carp (Cyprinus carpio) tissues and Epithelioma papulosum cyprinid (EPC) cells to establish experimental models of iron overload with FeCl3 or ferric amine citrate (FAC), and to establish experimental models of bacterial infection with Aeromonas hydrophila. The current research has successfully identified the CcTF-b gene in common carp, revealing an ORF of 2001 bp with N-terminal and C-terminal structures. CcTF-b exhibited inhibitory effects on the growth of LPS and LTA in vitro. In the experimental models, the upregulations of PTGS2a and PTGS2a-like mRNA and protein levels were observed. Overexpression or interference with CcTF-b levels can modulate the expression of ferroptosis-related genes, inflammatory cytokines, lipid reactive oxygen species, GSH/GSSH levels, and Fe2+ concentration. Significantly, the expression levels of Nrf2 and GPX4 mRNA and protein, as well as the bacterial load of A. hydrophila, could be also modulated either by upregulating or downregulating CcTF-b factors. In conclusion, in this study, these findings suggest that CcTF-b plays a critical role in the innate immune response of common carp.

Trimetazidine attenuates Ischemia/Reperfusion-Induced myocardial ferroptosis by modulating the Sirt3/Nrf2-GSH system and reducing Oxidative/Nitrative stress

Ferroptosis is a newly defined mode of cellular demise. The increasing investigation supports that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia–reperfusion (I/R) injury. Hence, targeting ferroptosis is a novel strategy for treating myocardial injury. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. This study aimed to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. To this end, researchers have constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. Here, I/R mediated the onset of ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated cardiomyocyte injury. Mechanistically, we found that TMZ upregulated the expression of Sirt3. Therefore, we used si-Sirt3 and 3-TYP to interfere with Sirt3 action in vitro and in vivo, respectively. Both si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. These results indicate that TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway. Our study offers insights into the mechanism underlying the cardioprotective benefits of TMZ and establishes a groundwork for expanding its potential applications.

Ferroptosis contributes to the development of cardiac dysfunction in iron overload cardiomyopathy

Abstract Background Ferroptosis is a novel form of cell death, and its role in iron overload cardiomyopathy (IOC) has not been elucidated. Purpose To explore whether ferroptosis of cardiomyocytes contributes to cardiac dysfunction in IOC by cardiac MR (CMR) and molecular biology techniques in vivo. Methods A total of 14 Sprague-Dawley (SD) rats were randomly divided into two groups: the control group (n=6) and the IOC group (n=8). The latter was induced by intraperitoneal injection of iron dextran on alternate days for 9 weeks and underwent a 7T CMR for assessment of cardiac function, including left ventricular ejection fraction (LVEF) and global longitude strain (GLS), along with the assessment of iron overload severity and fibrosis using Cine, T2 mapping, and late gadolinium enhancement (LGE), respectively. Circulating iron overload was determined via blood biochemistry analysis, measuring serum iron, ferritin, and transferrin levels. Furthermore, Prussian blue and Masson staining were employed to identify iron and fibrosis deposition within the myocardium, respectively. Cardiac ultrastructure, especially mitochondria, was examined via transmission electron microscopy (TEM). A sensitive fluorescent probe, dihydroethidium (DHE), was employed for the detection of reactive oxygen species (ROS) levels. Malondialdehyde (MDA), prostaglandin-endoperoxide synthase 2 (PTGS2), and glutathione peroxidase 4 (GPX4) were utilized to identify and quantify levels of lipid peroxidation, thereby providing comprehensive insights into cardiac cellular ferroptosis. Results 6 rats survived in the control group and 5 in the IOC group. Compared with the control group, the IOC rats had reduced T2 values of the cardiac septum (P<0.001), with normal LVEF (P>0.05) but decreased GLS (P<0.01), seen in Fig 1A. Based on blood biochemistry and Prussian blue staining, they were evident that IOC rats exhibited both circulating and cardiac iron overload, as seen in Figure 1B, C. Masson staining showed no obvious myocardial fibrosis, which was consistent with negative CMR LGE results, seen in Fig 1A, B. TEM further elucidated cardiac mitochondrial injuries in IOC rats, including focal vacuolization, swelling, crest disruption, and even disappearance, seen in Fig 2A. The fluorescent probe results revealed a striking increase in red fluorescence within the myocardium of IOC rats, seen in Fig 2B. Additionally, IOC rats exhibited significantly elevated levels of MDA and PTGS2mRNA (P<0.001), accompanied by notable downregulation of GPX4mRNA expression (P<0.001), seen in Fig 2C. These findings suggested the occurrence of ferroptosis in the myocardium of IOC rats. Conclusions In IOC, ferroptosis rather than necrosis is the primary driver of cardiac dysfunction, which is characterized by maintaining normal LVEF but experiencing a reduction in GLS without accompanying myocardial fibrosis. Our study sheds light on the potential involvement of ferroptosis in the pathogenesis of IOC.

Iron chelation therapy failed to improve cardiac dysfunction caused by mitochondrial injury in rats with iron overload cardiomyopathy a 7T Cardiac MR research in vivo

Abstract Purpose To assess the efficacy of iron chelation therapy in improving cardiac function in iron overload cardiomyopathy (IOC) rats by using Cardiac magnetic resonance feature-tracking (CMR-FT). Methods The IOC rat model was induced by intraperitoneal injection of iron dextran over 2 months. Subsequently, 7 rats with IOC were assigned as IOC group to receive continued intraperitoneal injections of saline for an additional 2 months, while another group of 5 rats received intraperitoneal injections of deferoxamine (DFO) for the same duration, forming the IOC+DFO group. Meanwhile, a control group consisting of 7 healthy rats received intraperitoneal injections of saline for the entire duration of 4 months. All rats underwent a 7T CMR scan to assess cardiac function, myocardial iron overload, and myocardial fibrosis via cine, T2 mapping, and late gadolinium enhancement (LGE) scanning, respectively. The cardiac function analysis included left ventricular ejection fraction (LVEF) and left ventricular global longitudinal strain (GLS) using cine images. Following CMR scans, all rats underwent open-chest blood collection to detect serum iron levels, and cardiac gross specimens were then subjected to pathological staining, including hematoxylin and eosin (HE) for cardiomyocytes injury, Prussian blue for iron deposition , and Masson staining for myocardial fibrosis. Furthermore, the ultrastructure of cardiomyocyte was examined using transmission electron microscopy (TEM). Results The T2 value, measured in the septum wall at the mid-layer of the LV, and LVEF, and GLS exhibited a significant decrease in the IOC or IOC+DFO group, compared to the control group, while there were no significant difference observed between the IOC and IOC+DFO group (Fig. 1A, B, C). Myocardial fibrosis was not detected in the LGE images in both IOC and IOC+DFO group. Compared to the control group (37.5±12.5μmol/L) , serum iron levels were significantly elevated in the IOC group (368.6±181.0μmol/L) and in chelation treatment group (106.1±32.2μmol/L). Histological examination with HE staining revealed a normal arrangement of myocardial cells in all rats, without cellular degeneration or necrosis. Prussian blue staining highlighted the presence of iron particles within the myocardial interstitium in the IOC and IOC+DFO groups. Masson staining demonstrated intact myocardial muscle bundles without any evidence of myocardial fibrosis. Transmission electron microscopy (TEM) revealed myocardial mitochondria injury, characterized by ruptured outer membranes, reduced cristae, and vacuolization. Conclusions Following iron chelation therapy, the excessive iron burden in the bloodstream was alleviated. However, myocardial iron overload persisted in IOC rats, with no significant improvement in cardiac function observed. This persistence may be attributed to mitochondrial injury. The findings underscore the importance of monitoring cardiac dysfunction in patients with iron overload.CMR parameters analysis in IOC rats

The contribution of SLC7A11-mediated ferroptosis to cardiac injury in iron overload cardiomyopathy: an in vitro study

Abstract Background Recent studies have indicated that iron overload can induce myocardial ferroptosis in iron overload cardiomyopathy (IOC), but the specific mechanisms, including the role of SLC7A11, remain unclear. Purpose By delving into the role of SLC7A11-mediated ferroptosis in IOC, this research endeavors to provide novel insights and therapeutic strategies for understanding and treating IOC. Methods To induce an in vitro model of IOC, wild-type rat cardiomyocytes (H9C2) were cultured in a ferric citrate (FAC) medium. Cardiomyocytes were exposed to various concentrations of iron overload (ranging from 0 mM to 2 mM) for durations of 4, 8, 12, and 24 hours. Cell viability at different FAC concentrations was assessed by the cell counting kit-8 (CCK8) assay and the level of the ferroptosis indicator malondialdehyde (MDA) was measured to determine the optimal concentration and duration of FAC treatment which was required to establish the IOC cell model. Next, ferroptosis indicators, including MDA, prostaglandin peroxide synthase 2 (PTGS2), and glutathione peroxidase 4 (GPX4), and the pivotal factor, SLC7A11 of IOC cardiomyocytes were evaluated. The protein and mRNA levels of SLC7A11 were assessed by molecular biology techniques. Additionally, the mitochondrial morphology of the IOC cardiomyocytes was meticulously examined by transmission electron microscopy (TEM). Flow cytometry was employed for detecting reactive oxygen species (ROS) levels. Furthermore, we elucidated the underlying mechanism of myocardial injury in IOC by overexpressing SLC7A11 and subsequently detecting changes in ferroptosis markers. Results CCK-8 results showed that the viability of cardiomyocytes exhibited dose-dependently with increasing FAC concentration (R2=0.5483, p<0.0001). Furthermore, the viability of cardiomyocytes remained relatively stable, with survival rates of approximately 50% and not decreasing below 50%. Additionally, the MDA content in IOC cardiomyocytes increased dose-dependently with the elevation of FAC concentration (R2=0.75, p<0.05), with a significant increase observed at 0.75mM. Expression levels of ferroptosis marker genes, GPX4 and PTGS2, both at the mRNA and protein levels, are indicative of diminished antioxidant capacity. Meanwhile, the level of myocardial MDA and ROS were markedly elevated, indicating underscoring increased oxidative stress within the IOC cardiomyocytes. Moreover, there was a downregulation in the expression of SLC7A11 mRNA and protein in IOC cardiomyocytes, suggesting a potential compensatory mechanism to counteract oxidative damage. TEM further elucidated cardiac mitochondrial injuries in IOC rats, including focal vacuolization, swelling, crest disruption, and even disappearance. Overexpression of SLC7A11 resulted in a significant augmentation of GPX4 and a reduction of PTGS2mRNA and protein expression levels. Conclusions Ferroptosis, mediated by SLC7A11, may represent a pivotal mechanism underlying myocardial injury in IOC.

The gut microbiota metabolite trimethylamine-N-oxide in children with β-thalassemia: potential implication for iron-induced renal tubular dysfunction.

Renal tubular dysfunction is common in transfusion-dependent β thalassemia (β-TM). Iron overload, chronic anemia, and hypoxia are precipitating factors for renal insult. However, gut microbiota engagement in the renal insult has not been explored. Our work aimed to assess the potential link between iron overload, gut leakage/dysbiosis, and kidney dysfunction in these children. We enrolled 40 children with β-TM and 40 healthy controls. Gut leakage/dysbiosis biomarkers (trimethylamine-N-oxide [TMAO] and fecal short-chain fatty acids [SCFAs]), oxidative stress and inflammatory biomarkers, TMAO-regulated proteins such as serum sirtuin 1 (S.SIRT1) and serum high mobility box group-1 (S.HMGB1), and tubular dysfunction biomarkers were assessed. Correlations and regression analysis were performed to assess the relation between different parameters. Iron overload, redox imbalance, and generalized inflammation were evident in children with β-TM. Renal tubular dysfunction biomarkers and S.TMAO were significantly elevated in the patient group. Furthermore, fecal SCFAs were significantly lower with upregulation of the investigated genes in the patient group. The correlation studies affirmed the close relationship between circulating ferritin, TMAO, and renal dysfunction and strongly implicated SIRT1/HMGB1 axis in TMAO action. Gut dysbiosis may have a role in the pathogenesis of renal injury in children with β-TM. Renal tubular dysfunction is a prominent health issue in β thalassemia major (β-TM). Iron overload, chronic anemia, and hypoxia are known precipitating factors. However, gut microbiota engagement in renal insult in these patients has not yet been explored. We aimed to assess potential link between iron overload, gut leakage/dysbiosis, and kidney dysfunction in β-TM children and to highlight the SIRT1/HMGB1 axis, a signal motivated by the gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO), involvement in such insults. We found that gut leakage/dysbiosis may have a role in kidney dysfunction in β-TM children by exacerbating the iron-motivated oxidative stress, inflammation, ferroptosis, and modulating SIRT1/HMGB1 axis.

Iron overload is positively associated with the incidence of osteoarthritis: A NHANES cross-sectional study.

With the aging of the global population and the increase in the number of people with conditions such as obesity, the incidence of osteoarthritis (OA) is increasing annually. Clinical studies have shown that excessive accumulation of iron in joints is associated with age-related OA. However, there have been no reports on the relationship between iron metabolism and osteoarthritis. A STROBE-compliant cross-sectional observational study, was carried out and analyzed from the National Health and Nutrition Examination Survey from 2001 to 2020, including data on serum iron, transferrin saturation, serum ferritin, total iron-binding capacity, and transferrin receptors, as well as data on osteoarthritis. This cross-sectional study was conducted to explore the relationship between serum iron levels, osteoarthritis, and related metabolic factors. By adjusting the model and using quantile logistic regression models, the interaction between human body iron content and the aforementioned variables was analyzed. A total of 56,323 participants over 5 cycles were assessed for iron levels. After adjusting the model for age, sex, race, education level, marital status, total energy intake, physical activity, drinking, BMI, smoking, hypertension, and diabetes, we found that in different quantile regression results, serum iron was associated with OA, Q4: OR = 1.231 (95%CI: 1.009-1.501, P < .05). Ferritin is associated with OA, Q2: OR = 1.309 (95%CI: 1.012-1.692, P < .05); Q3: OR = 1.424 (95%CI: 1.129-1.797, P < .01); Q4: OR = 1.280 (95%CI: 1.013-1.616, P < .05). This cross-sectional study found that serum iron and transferrin saturation levels were positively correlated with OA incidence, suggesting that iron overload is a risk factor for OA. Large-sample prospective cohort studies are needed to confirm the correlation between iron overload and OA.

Computed Tomography and Magnetic Resonance Imaging in Liver Iron Overload: From Precise Quantification to Prognosis Assessment

Liver iron overload is associated with conditions such as hereditary hemochromatosis, thalassemia major, and chronic liver diseases. The liver-related outcomes, patient outcomes, and treatment recommendations of these patients differ depending on the cause and extent of iron overload. Accurate quantification of the liver iron concentration (LIC) is critical for effective patient management. This review focuses on the application of computed tomography (CT) and magnetic resonance imaging (MRI) for the precise quantification and prognostic assessment of liver iron overload. In recent years, the use of dual-energy CT and the emergence of MRI-based sequences (such as UTE, QSM, Dixon, and CSE technologies) have significantly increased the potential for noninvasive liver iron quantification. However, the establishment of internationally standardized imaging parameters, postprocessing procedures, and reporting protocols is urgently needed for better management of patients with liver iron overload.

GDF2 and BMP10 coordinate liver cellular crosstalk to maintain liver health

The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.

Impact of met-haemoglobin and oxidative stress on endothelial function in patients with transfusion dependent β-thalassemia

Transfusion dependent β-thalassemia is a genetic blood disorder characterized by chronic anaemia. Blood transfusion is lifesaving but comes at a cost. Iron overload emerges as a prime culprit as a free radicals damage endothelial cells. Chronic anaemia further disrupts oxygen delivery, exacerbating the oxidative stress. Increased levels of met-haemoglobin and malondialdehyde compromise endothelial function. This research sheds light on the impact of met-haemoglobin and oxidative stress on endothelial function in 50 patients with transfusion dependent β-thalassemia major compared to 50 healthy individuals as control. Blood samples were collected & subjected to CBC, biochemical analysis including creatinine, ferritin, CRP, LDH, and HCV antibodies. Oxidative stress was assessed using met-haemoglobin & malondialdehyde. Endothelial dysfunction was evaluated by endothelial activation and stress index (EASIX). EASIX, met-haemoglobin and malondialdehyde were significantly increased in patients (1.44 ± 0.75, 2.07 ± 0.2, 4.8 ± 0.63; respectively) compared to the control (0.52 ± 0.24,0.88 ± 0.34,0.8 ± 0.34; respectively). Significant strong positive correlation was found between EASIX and met-haemoglobin, malondialdehyde, serum ferritin and CRP (P = 0.00, r = 0.904, P = 0.00, r = 0.948, P = 0.00, r = 0.772, P = 0.00, r = 0.971; respectively. Met-haemoglobin as well as EASIX should be routinely estimated to assess endothelial function especially before the decision of splenectomy. Antioxidant drugs should be supplemented.

GDF2 and BMP10 coordinate liver cellular crosstalk to maintain liver health.

The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.

Abbreviated Multiparametric MR Solution (the “Liver Triple Screen”), the Future of Non-Invasive MR Quantification of Liver Fat, Iron, and Fibrosis

Background/Objectives: To review the findings of a multiparametric MRI (the “liver triple screen”) solution for the non-invasive assessment of liver fat, iron, and fibrosis in patients with chronic liver disease (CLD). Methods: A retrospective evaluation of all consecutive triple screen MRI cases was performed at our institution over the last 32 months. Relevant clinical, laboratory, and radiologic data were analyzed using descriptive statistics. Results: There were 268 patients, including 162 (60.4%) males and 106 (39.6%) females. The mean age was 54 ± 15.2 years (range 16 to 71 years). The most common cause of CLD was metabolic dysfunction-associated steatotic liver disease (MASLD) at 45.5%. The most common referring physician group was Gastroenterology at 62.7%. In 23.9% of cases, the reason for ordering the MRI was a pre-existing failed or unreliable US elastography. There were 17 cases (6.3%) of MRI technical failure. Our analysis revealed liver fibrosis in 66% of patients, steatosis in 68.3%, and iron overload in 22.1%. Combined fibrosis and steatosis were seen in 28.7%, steatosis and iron overload in 16.8%, fibrosis and iron overload in 6%, and combined fibrosis, steatosis, and iron overload in 4.1%. A positive MEFIB index, a predictor of liver-related outcomes, was found in 57 (27.5%) of 207 patients. Incidental findings were found in 14.9% of all MRIs. Conclusions: The liver triple screen MRI is an effective tool for evaluating liver fat, iron, and fibrosis in patients with CLD. It provides essential clinical information and can help identify MASLD patients at risk for liver-related outcomes.

Hepatitis B Virus-Associated Liver Carcinoma: The Role of Iron Metabolism and Its Modulation.

Hepatitis B virus (HBV) infection is a significant contributor to the development of hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide. Iron, a central co-factor in various metabolic pathways, plays an essential role in liver function, but its dysregulation can lead to severe health consequences. Accumulation of iron within hepatic cells over time is linked to increased liver injury and is strongly associated with sensitive exposure to a range of conditions, including cirrhosis, fibrosis and ultimately, HCC. This review explores the intricate interplay between iron metabolism and HCC within the context of HBV infection. Hepatic iron overload can arise from liver injury and disruptions in iron homeostasis, causing hepatic necrosis, inflammation, and fibrosis, ultimately culminating in carcinogenesis. Moreover, alterations in serum iron components in HBV-related scenarios have been observed to impact the persistence of HBV infection. Notably, the progression of HBV-associated liver damage exhibits distinct characteristics at various stages of liver disease. In addition to elucidating the complex relationship between iron metabolism and HCC in the context of HBV infection, this review also investigates the prognostic implications of systemic iron levels for HCC. Furthermore, it aims to provide a comprehensive understanding of the intricate interplay between iron metabolism and HCC, extending the discussion to the context of hepatitis C virus (HCV) infection. By shedding light on these multifaceted connections, this review aims to contribute to our understanding of the pathogenesis of HBV-associated HCC and potentially identify novel therapeutic avenues for intervention.

Ferulic Acid Alleviates Lipid and Bile Acid Metabolism Disorders by Targeting FASN and CYP7A1 in Iron Overload-Treated Mice

Iron overload is a common complication in various chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD). Lipid and bile acid metabolism disorders are regarded as crucial hallmarks of NAFLD. However, effects of iron accumulation on lipid and bile acid metabolism are not well understood. Ferulic acid (FA) can chelate iron and regulate lipid and bile acid metabolism, but its potential to alleviate lipid and bile acid metabolism disorders caused by iron overload remains unclear. Here, in vitro experiments, iron overload induced oxidative stress, apoptosis, genomic instability, and lipid deposition in AML12 cells. FA reduced lipid and bile acid synthesis while increasing fatty acid β-oxidation and bile acid export, as indicated by increased mRNA expression of PPARα, Acox1, Adipoq, Bsep, and Shp, and decreased mRNA expression of Fasn, Acc, and Cyp7a1. In vivo experiments, FA mitigated liver injury in mice caused by iron overload, as indicated by reduced AST and ALT activities, and decreased iron levels in both serum and liver. RNA-seq results showed that differentially expressed genes were enriched in biological processes related to lipid metabolism, lipid biosynthesis, lipid storage, and transport. Furthermore, FA decreased cholesterol and bile acid contents, downregulated lipogenesis protein FASN, and bile acid synthesis protein CYP7A1. In conclusion, FA can protect the liver from lipid and bile acid metabolism disorders caused by iron overload by targeting FASN and CYP7A1. Consequently, FA, as a dietary supplement, can potentially prevent and treat chronic liver diseases related to iron overload by regulating lipid and bile acid metabolism.

Exploring alterations of gut/blood microbes in addressing iron overload-induced gut dysbiosis and cognitive impairment in thalassemia patients

Iron overload causes cognitive impairment in thalassemia patients. The gut-brain axis plays an important role in cognitive function. However, the association between gut/blood microbiome, cognition, and iron burden in thalassemia patients has not been thoroughly investigated. We aimed to determine those associations in thalassemia patients with different blood-transfusion regimens. Sixty participants: healthy controls, transfusion-dependent thalassemia (TDT) patients, and non-transfusion-dependent (NTDT) patients, were recruited to evaluate iron overload, cognition, and gut/blood microbiome. TDT patients exhibited greater iron overload than NTDT patients. Most thalassemia patients developed gut dysbiosis, and approximately 25% of the patients developed minor cognitive impairment. Increased Fusobacteriota and Verrucomicrobiota with decreased Fibrobacterota were observed in both TDT and NTDT groups. TDT patients showed more abundant beneficial bacteria: Verrucomicrobia. Iron overload was correlated with cognitive impairment. Increased Butyricimonas and decreased Paraclostridium were associated with higher cognitive function. No trace of blood microbiota was observed. Differences in blood bacterial profiles of thalassemia patients and controls were insignificant. These findings suggest iron overload plays a role in the imbalance of gut microbiota and impaired cognitive function in thalassemia patients. Harnessing probiotic potential from those microbes could prevent the gut-brain disturbance in thalassemia patients.

Genetic iron overload aggravates and pharmacological iron restriction improves MDS pathophysiology in preclinical study

Although iron overload is a common feature in myelodysplastic syndromes (MDS), it remains unclear how iron excess is detrimental for disease pathophysiology. Taking advantage of complementary approaches, we analyzed the impact of iron overload and restriction achieved through genetic activation (FPNC326S) and pharmacologic inhibition (vamifeport) of the iron exporter ferroportin in a MDS mouse model, respectively. While FPNC326S-induced iron overload did not significantly improve the late stages of erythroid maturation, vamifeport-mediated iron restriction ameliorated anemia and red blood cell maturation in MDS mice, through the reduction of oxidative stress and apoptosis in erythroid progenitors. Iron overload aggravated and restriction alleviated ROS formation, DNA damage and cell death in hematopoietic stem and progenitor cells, resulting in altered cell survival and quality. Finally, myeloid bias, indicated by expanded bone marrow myeloid progenitors and circulating immature myeloid blasts, was exacerbated by iron excess and attenuated by iron restriction. Overall, vamifeport treatment resulted in improved anemia and significant survival increment in MDS mice. Interestingly, the combined therapy with vamifeport and the erythroid maturation agent luspatercept has superior effect in improving anemia and myeloid bias as compared to single treatments, and offers additive beneficial effects in MDS. Our results prove for the first time in a preclinical model that iron plays a pathologic role in transfusion-independent MDS. This is likely aggravated by transfusional iron overload, as suggested by observations in the FPNC326SMDS model. Ultimately, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS.

SAT1/ALOX15 Signaling Pathway Is Involved in Ferroptosis After Skeletal Muscle Contusion

Skeletal muscle contusion (SMC) is common in daily life and clinical practice, but the molecular mechanisms underlying SMC healing are unclear. Ferroptosis, a regulated cell death type, has gained attention recently. We observed iron overload in skeletal muscle following contusion through HE and Perls staining. Abnormal iron levels are highly likely to induce ferroptosis. Therefore, we aimed to explore whether iron overload after contusion leads to ferroptosis in skeletal muscle and the underlying mechanisms, which will help us understand the effects of iron abnormalities on skeletal muscle repair. Initially, we searched SMC gene expression profiles from the GEO database and used bioinformatics analysis to reveal ferroptosis occurrence. Then, we identified the gene sat1 plays an important role in this process. We further established a rat SMC model and treated rats with ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). Our findings confirmed iron overload from SMC can lead to ferroptosis in rats. We also demonstrated that SAT1 can regulate ferroptosis by affecting ALOX15. Moreover, we constructed a ferroptosis L6 cell model and found that SAT1 knockdown significantly inhibited ALOX15 expression and reduced cellular lipid peroxidation. In conclusion, these results indicated ferroptosis can occur following SMC, and SAT1, as a key regulator, affects skeletal muscle injury healing by mediating high ALOX15 expression, which in turn regulates lipid peroxidation.

Streptomyces sp. from desert soil as a biofactory for antioxidants with radical scavenging and iron chelating potential

Iron homeostasis is vital for normal physiology, but in the majority of circumstances, like iron overload, this equilibrium is upset leading to free iron in the plasma. This condition with excess iron is known as hemochromatosis, which has been linked to many side effects, including cancer and liver cirrhosis. The current research aimed to investigate active molecules from Streptomyces sp. isolated from the extreme environment of Bahawalpur deserts. The strain was characterized using 16 S rRNA sequencing. Chemical analysis of the ethyl acetate cure extract revealed the presence of phenols, flavonoids, alkaloids, and tannins. Multiple ultraviolet (UV) active metabolites that were essential for the stated pharmacological activities were also demonstrated by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC). Additionally, Gas chromatography/mass spectrometry (GC-MS) analysis revealed the primary constituents of the extract to compose of phenol and ester compounds. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to assess the extract’s antioxidant capacity, and the results showed a good half-maximal inhibitory concentration (IC50) value of 0.034 µg/mL in comparison to the positive control ascorbic acid’s 0.12 µg/mL. In addition, iron chelation activity of extract showed significant chelation potential at 250 and 125 µg/mL, while 62.5 µg/mL showed only mild chelation of the ferrous ion using ethylene diamine tetra acetic acid (EDTA) as a positive control. Likewise, the extract’s cytotoxicity was analyzed through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using varying concentrations of the extract and showed 51% cytotoxicity at 350 µg/mL and 65% inhibition of cell growth at 700 µg/mL, respectively. The bioactive compounds from Streptomyces sp. demonstrated strong antioxidant and iron chelating potentials and can prolong the cell survival in extreme environment.