Iron overload and related oxidative damage are seen in many rare diseases, due to mutation of iron homeostasis-related genes. As a core regulator on cellular antioxidant reaction, Nrf2 can also decrease systemic and cellular iron levels by regulating iron-related genes and pathways, making Nrf2 activators very good candidates for the treatment of iron overload disorders. Successful examples include the clinical use of omaveloxolone for Friedreich's Ataxia and dimethyl fumarate for relapsing-remitting multiple sclerosis. Despite these uses, the therapeutic potentials of Nrf2 activators for iron overload disorders may be overlooked in clinical practice. Therefore, this study talks about the potential use, possible mechanisms, and precautions of Nrf2 activators in treating rare iron overload diseases. In addition, a combination therapy with Nrf2 activators and iron chelators is proposed for clinical reference, aiming to facilitate the clinical use of Nrf2 activators for more iron overload disorders.

Chronic kidney disease (CKD) is a condition characterized by abnormalities in kidney structure and function that persist for more than 3 months. It is estimated that more than 800 million people in the world have a diagnosis of CKD. To remove the harmful metabolic substances from the body, people with CKD need to perform hemodialysis. Due to their beneficial effects against a wide range of clinical conditions, physical exercise is considered a non-pharmacological therapy. This study aimed to evaluate the beneficial effects of resistance exercise during hemodialysis on metabolic adipokines, myokines, body weight, and glomerular filtration rate in patients living with CKD. Briefly, the blood samples were collected in two moments: immediately before the start of the resistance exercise protocol and 1 week after the end of the protocol. Resistance exercise protocol was performed thrice a week for 12 weeks and applied during hemodialysis sessions. Here, resistance exercise increases the circulating irisin (14.56%; p = 0.0112), handgrip strength (5.70%; p = 0.0036), glomerular filtration rate (25.9%; p = 0.022) and significantly decreases adiponectin (- 55.7%; p = 0.0044), body weight (- 3.7%; p = 0.0001), glucose (- 22%; p = 0.009), and albumin levels (- 9.55%; p = 0.0001). Conversely, leptin levels (- 10.9%; p = 0.38), iron (3.05%; p = 0.705), ferritin (3.24%; p = 0.880), hemoglobin (- 0.52%; p = 0.75), total cholesterol (7.9%; p = 0.19), LDL (- 9.99%; p = 0.15) and HDL (- 4.8%; p = 0.45), did not change after resistance exercise. Interestingly, 1,25 hydroxyvitamin D levels were significantly increased (14.5%; p = 0.01) following resistance exercise. Considering the effect of sex (males vs. females), we found that irisin levels increased in females but not in males after the resistance exercise protocol. Furthermore, handgrip strength and body weight were different, indicating that males had the highest strength and weight. We demonstrated that both males and females had lower albumin levels after the resistance exercise protocol. In conclusion, we suggest that resistance exercise has beneficial effects in the CKD population by modulating adipokines and metabolic myokines and therefore can be used as a non-pharmacological adjunctive therapy in CKD patients undergoing HD.

Iron (Fe) is fundamental to life on earth. In the human body, it is both essential and harmful if above threshold. A similar balance applies to other elements: calcium (Ca), magnesium (Mg), and trace elements including copper (Cu), zinc (Zn), lead (Pb), cadmium (Cd), mercury (Hg), and nickel (Ni). These elements share some proteins involved in the absorption and transport of Fe. Cu and Cd can inhibit Fe absorption, while excess of Fe may antagonize Cu metabolism and reduce ceruloplasmin (Cp). Excessive Fe can hinder Zn absorption and transferrin (Trf) can bind to both Zn and Ni. Ca is able to inhibit the divalent metal transporter 1 (DMT1) in a dose-dependent manner to reduce Fe absorption and low Mg concentrations can exacerbate Fe deficiency. Pb competitively inhibits Fe distribution and elevated Cd absorption reduces Fe uptake. Exposure to Hg is associated with higher ferritin concentrations and Ni alters intracellular Fe metabolism. Fe removal by phlebotomy in hemochromatosis patients has shown to increase the levels of Cd and Pb and alter the concentrations of trace elements in some types of anemia. Yet, the effects of chronic exposure of most trace elements remain poorly understood.

The persistent organic pollutant perfluorooctane sulfonate (PFOS) is demonstrated to induce hepatotoxicity through disrupting iron homeostasis and subsequent ferroptosis in hepatocytes. However, it is still elusive in the mechanisms underneath the dysfunctional iron metabolism caused by PFOS. In this study, we observed that PFOS activated the nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in mice liver and human hepatocytes. PFOS reduced the ubiquitination of NCOA4, subsequently causing an increase in the expression of NCOA4. PFOS induced the ubiquitination of HECT and RLD domain-containing E3 ubiquitin protein ligase 2 (HERC2), an upstream negative regulator of NCOA4, leading to the degradation of HERC2. PFOS upregulated the level of detyrosinated α-tubulin (detyr-α-tubulin) in hepatocytes. Under PFOS exposure, detyr-α-tubulin interacted with tripartite motif containing 21 (TRIM21), another E3 ubiquitin ligase responsible for HERC2 degradation. Despite the reduction in the protein level of HERC2, the increases in detyr-α-tubulin and the interaction between detyr-α-tubulin and TRIM21 caused by PFOS facilitated the interaction between TRIM21 and HERC2. Furthermore, inhibiting α-tubulin detyrosination by parthenolide reversed the ferritinophagy and the following ferroptosis caused by PFOS. Collectively, this study points out the existence of ferritinophagy and enriches the understanding of the alteration in iron metabolism under PFOS exposure, providing novel mechanistic insights into the hepatic toxicity of PFOS.

Intracerebral hemorrhage (ICH) is associated with high rates of mortality and disability, underscoring an urgent need for effective therapeutic interventions. The clinical prognosis of ICH remains limited, primarily due to the absence of targeted, precise therapeutic options. Advances in novel drug delivery platforms, including nanotechnology, gel-based systems, and exosome-mediated therapies, have shown potential in enhancing ICH management. This review delves into the pathophysiological mechanisms of ICH and provides a thorough analysis of existing treatment strategies, with an emphasis on innovative drug delivery approaches designed to address critical pathological pathways. We assess the benefits and limitations of these therapies, offering insights into future directions in ICH research and highlighting the transformative potential of next-generation drug delivery systems in improving patient outcomes.

Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence.

Iron is an essential micronutrient for abounding physiological processes in the body, and its deficiency can be caused by various factors, such as low iron intake due to economic difficulties or loss of appetite, decreased iron absorption due to gastrointestinal issues, or increased iron loss due to hemorrhages or proteinuria. Iron deficiency is a prevalent issue among heart failure (HF) patients and is a significant contributor to anemia, affecting 30-50% of patients regardless of their gender, ethnicity, or left ventricular ejection fraction. Individuals with HF have high levels of pro-inflammatory cytokines, which can inhibit erythropoiesis by degrading the membrane iron exporter ferroportin, mediated by an increased release of hepcidin. In addition, elevated sympathetic and renin-angiotensin-aldosterone system activity retains salt and water, resulting in high cardiac output HF in people with normal left ventricular function. This review provides an overview of iron deficiency and HF.

Glaucoma, a leading cause of irreversible blindness worldwide, is characterized by the progressive degeneration of retinal ganglion cells (RGCs). While elevated intraocular pressure (IOP) significantly contributes to disease progression, managing IOP alone does not completely halt it. The mechanisms underlying RGCs loss in glaucoma remain unclear, but ferroptosis-an iron-dependent form of oxidative cell death-has been implicated, particularly in IOP-induced RGCs loss. There is an urgent need for neuroprotective treatments. Our previous research showed that hydrogen sulfide (H2S) protects RGCs against glaucomatous injury. This study aims to investigate the interplay between elevated pressure, mitochondrial dysfunction, iron homeostasis, and ferroptosis in RGCs death, focusing on how H2S may mitigate pressure-induced ferroptosis and protect RGCs. We demonstrate alterations in iron metabolism and mitochondrial function in a subacute IOP elevation model in vivo. In vitro, we confirm that elevated pressure, iron overload, and mitochondrial dysfunction lead to RGCs loss, increased retinal ferrous iron and total iron content, and heightened reactive oxygen species (ROS). Notably, pressure increases NADPH oxidase 2 (NOX2) and decreases glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. NOX2 deletion or inhibition by H2S prevents pressure-induced RGCs loss and ferroptosis. Our findings reveal that H2S chelates iron, regulates iron metabolism, reduces oxidative stress, and mitigates ferroptosis, positioning slow-releasing H2S donors are positioning as a promising multi-target therapy for glaucoma, with NOX2 emerging as a key regulator of ferroptosis.

Anemia is common among HIV/AIDS patients, impacting prognosis. Particulate matter (PM) exposure is an understudied, potentially modifiable risk factor in this group.

We gathered 36,266 hemoglobin (Hb) measurements from 6808 HIV/AIDS patients from the HIV/AIDS Comprehensive Response Information Management System from 1 January 2004 to 31 December 2021. We evaluated the relationship between Hb levels and short-term PM exposure using linear mixed-effects models. We used logistic regression to estimate the association of long-term PM exposure with baseline anemia prevalence and time-varying Cox models to estimate the association of long-term PM exposure with follow-up incidence of anemia. Mediation analysis explored the role of chronic kidney disease (CKD) in the association between PM exposure and anemia.

For every 5 µg/m³ increase in 28-day average PM 1 , Hb levels decreased by 0.43 g/l. For a 10 µg/m³ increase in PM 2.5 , Hb decreased by 0.55 g/l; for the same increase in PM 10, Hb decreased by 0.35 g/l. A 5 µg/m³ increase in 1-year average PM 1 corresponded to a 7% higher prevalence of anemia at baseline, a 10 µg/m³ increase in PM 2.5 to 8% higher prevalence, and a 10 µg/m³ increase in PM 10 to 6% higher prevalence. These rises in average PM concentrations during follow-up were associated with increased incident anemia by 54% (PM 1 ), 72% (PM 2.5 ), and 51% (PM 10 ). CKD partially mediated the positive associations between PM exposure and the incidence of anemia.

PM exposure was associated with lower Hb levels and higher incidence of anemia in HIV/AIDS patients and CKD with mediating estimated effects in PM-induced anemia.

SLC11A2 (DMT1) and SLC40A1 (ferroportin) are essential for dietary iron absorption, but their role in manganese transport is debated. SLC30A10 deficiency causes severe manganese excess due to loss of gastrointestinal manganese excretion. Patients are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here, we determine if divalent metal transport 1 (Dmt1) and ferroportin can transport manganese using Slc30a10-deficient mice as a model.

Manganese absorption and levels and other disease parameters were assessed in Slc30a10-/- mice with and without intestinal Dmt1 and ferroportin deficiency using gastric gavage, surgical bile collections, multiple metal assays, and other techniques. The contribution of intestinal Slc30a10 deficiency to ferroportin-dependent manganese absorption was explored by determining if intestinal Slc30a10 deficiency increases manganese absorption in a mouse model of hereditary hemochromatosis, a disease of iron excess due to ferroportin upregulation.

Manganese absorption was increased in Slc30a10-deficient mice despite manganese excess. Intestinal Dmt1 and ferroportin deficiency attenuated manganese absorption and excess in Slc30a10-deficient mice. Intestinal Slc30a10 deficiency increased manganese absorption and levels in the hemochromatosis mouse model.

Aberrant absorption contributes prominently to SLC30A10 deficiency, a disease previously attributed to impaired excretion, and is dependent upon intestinal Dmt1 and ferroportin and exacerbated by loss of intestinal Slc30a10. This work expands our understanding of overlaps between manganese and iron transport and the mechanisms by which the body regulates absorption of 2 nutrients that can share transport pathways. We propose that a reconsideration of the role of Dmt1 and ferroportin in manganese homeostasis is warranted.

Diabetic kidney disease (DKD) is a prevalent complication of diabetes mellitus (DM), and its incidence is increasing alongside the number of diabetes cases. Effective treatment and long-term management of DKD present significant challenges; thus, a deeper understanding of its pathogenesis is essential to address this issue. Chronic inflammation and abnormal cell death in the kidney closely associate with DKD development. Recently, there has been considerable attention focused on immune cell infiltration into renal tissues and its inflammatory response's role in disease progression. Concurrently, ferroptosis-a novel form of cell death-has emerged as a critical factor in DKD pathogenesis, leading to increased glomerular filtration permeability, proteinuria, tubular injury, interstitial fibrosis, and other pathological processes. The cardiorenal benefits of SGLT2 inhibitors (SGLT2-i) in DKD patients have been demonstrated through numerous large clinical trials. Moreover, further exploratory experiments indicate these drugs may ameliorate serum and urinary markers of inflammation, such as TNF-α, and inhibit ferroptosis in DKD models. Consequently, investigating the interplay between ferroptosis and innate immune and inflammatory responses in DKD is essential for guiding future drug development. This review presents an overview of ferroptosis within the context of DKD, beginning with its core mechanisms and delving into its potential roles in DKD progression. We will also analyze how aberrant innate immune cells, molecules, and signaling pathways contribute to disease progression. Finally, we discuss the interactions between ferroptosis and immune responses, as well as targeted therapeutic agents, based on current evidence. By analyzing the interplay between ferroptosis and innate immunity alongside its inflammatory responses in DKD, we aim to provide insights for clinical management and drug development in this area.

Iron limitation plays a fundamental role in host immunity against Salmonella infection. The mechanisms by which Salmonella antagonizes nutritional immunity, particularly those regulated by small non-coding RNAs (sRNAs), remain incompletely understood. In this study, we investigated the role of a previously identified sRNA, Salmonella adhesive-associated sRNA (SaaS), in host iron metabolism. Utilizing a combined BALB/c mouse model and HepG2 cell model, we demonstrated that SaaS enhances hepcidin synthesis via the bone morphogenetic protein (BMP)-SMAD pathway, leading to decreased ferroportin 1 level. This suppression of ferroportin 1 results in reduced serum iron and increased hepatic iron accumulation, ultimately causing iron-deficiency anemia. The accumulation of iron triggers hepatic oxidative stress, exacerbating liver damage. Concurrently, SaaS activates the signal transducer and activator of transcription 3 (STAT3) pathway in a triggering receptor expressed on myeloid cells-1 (TREM1)-interleukin (IL)-6-dependent manner, intensifying the inflammatory response. Collectively, these results provide evidence that sRNAs serve as crucial regulators of Salmonella pathogenesis and underscore the potential of targeting sRNAs for the prevention of salmonellosis.

The best timing for evaluation of anemia is not well defined and the clinical yield of performing workup during non-anemia-related hospitalization is unclear. We aimed to evaluate the prognostic value of inpatient laboratory anemia evaluation.

This was a retrospective propensity-matched cohort study between the years 2013-2022 in Rabin Medical Center Israel. We included all patients admitted for non-anemia-related reasons and were found to be anemic. Patients were divided into groups based on basic laboratory anemia evaluation. Outcomes were cancer diagnosis, colonoscopy rate, duration of admission, and all-cause mortality. Multivariable analysis with competing risk of death was performed and a p-value of 5 % was considered significant.

Following matching, 4,238 patients were included in the evaluation group compared to 7,680 in the no-evaluation group. In-patient laboratory anemia evaluation was associated with gastrointestinal cancer and any cancer diagnosis - HR of 1.53 (95 % CI, 1.15- 2.05) and HR of 1.23 (95 % CI, 1.11-1.37) respectively. The rate of colonoscopy was higher, and anemia prevalence was lower in the evaluation group after 1-year follow-up. Intravenous iron treatment was more prevalent in the evaluation group. The laboratory anemia evaluation prolonged the admission (5 vs 4 days). There was no difference in the all-cause mortality across the 10-year follow-up.

Inpatient anemia evaluation with basic laboratory tests was found to be associated with an increase in outpatient gastrointestinal cancer diagnosis and showed clinical and diagnostic advantages. For patients who can benefit from early gastrointestinal cancer diagnosis, admission holds a valid opportunity to initiate the evaluation.

Blood-based assays are expected to be integrated into clinical routines across various contexts, including Alzheimer's disease (AD). Vascular dementia (VaD), which is the second most common cause leading to dementia after AD, could also significantly benefit from this advancement. However, no informative fluid biomarker has been identified for VaD. Given the disruption of iron homeostasis in both AD and VaD, this study aims to characterize the potential of the iron-related hormone Hepcidin as a biomarker for these two conditions. We will compare its added value to established AT(N) blood biomarkers.

Blood biomarkers (amyloid-composite, p-Tau181, Neurofilament Light Chain [NfL] and Hepcidin) levels in blood were analyzed in two independent cohorts and compared between AD patients and non-AD individuals. Additionally, blood Hepcidin and NfL were evaluated in the contexts of VaD and CADASIL, with their relative diagnostic value assessed.

Blood Hepcidin and NfL do not significantly increase the AUC obtained with both p-Tau181 and amyloid composite in the context of AD. In contrast, AUC for VaD diagnosis is significantly higher when combining these two blood biomarkers compared to NfL alone. Hepcidin was not significantly modified in CADASIL patients compared to control subjects.

Blood Hepcidin and NfL have limited interest in the clinical context of AD but determination of these biomarkers shows to be highly informative for the diagnosis of VaD. This result could have important implications for diagnosis and implementation of clinical trials.

The liver hormone hepcidin regulates systemic iron homeostasis to provide enough iron for vital processes while limiting toxicity. Hepcidin acts by degrading its receptor ferroportin (encoded by Slc40a1) to decrease iron export to plasma. Iron controls hepcidin production in part by inducing liver endothelial cells (LECs) to produce bone morphogenetic proteins (BMPs) that activate hepcidin transcription in hepatocytes. Here, we used in vitro and in vivo models to investigate whether ferroportin contributes to LEC intracellular iron content to modulate BMP expression and, thereby, hepcidin. Quantitative proteomics of LECs from mice fed different iron diets demonstrated an inverse relationship between dietary iron and endothelial ferroportin expression. Slc40a1 knockdown primary mouse LECs and endothelial Slc40a1 knockout mice exhibited increased LEC iron and BMP ligand expression. Endothelial Slc40a1 knockout mice also exhibited altered systemic iron homeostasis with decreased serum and total liver iron but preserved erythropoiesis. Although endothelial Slc40a1 knockout mice had similar hepcidin expression to control mice, hepcidin levels were inappropriately high relative to iron levels. Moreover, when iron levels were equalized with iron treatment, hepcidin levels were higher in endothelial Slc40a1 knockout mice than in controls. Finally, LEC ferroportin levels were inversely correlated with hepcidin levels in multiple mouse models, and treatment of hepcidin-deficient mice with mini-hepcidin decreased LEC ferroportin expression. Overall, these data show that LEC ferroportin modulates LEC iron and consequently BMP expression to influence hepcidin production. Furthermore, LEC ferroportin expression is regulated by hepcidin, demonstrating a bidirectional communication between LECs and hepatocytes to orchestrate systemic iron homeostasis.

Maintaining iron homeostasis is necessary for kidney functioning. There is more and more research indicating that kidney disease is often caused by iron imbalance. Over the past decade, ferroptosis' role in mediating the development and progression of renal disorders, such as acute kidney injury (renal ischemia-reperfusion injury, drug-induced acute kidney injury, severe acute pancreatitis induced acute kidney injury and sepsis-associated acute kidney injury), chronic kidney disease (diabetic nephropathy, renal fibrosis, autosomal dominant polycystic kidney disease) and renal cell carcinoma, has come into focus. Thus, knowing kidney iron metabolism and ferroptosis regulation may enhance disease therapy. In this review, we discuss the metabolic and molecular mechanisms of iron signaling and ferroptosis in kidney disease. We also explore the possible targets of ferroptosis in the therapy of renal illness, as well as their existing limitations and future strategies.

Excess body iron (Fe) accrual is linked to chronic diseases. East Asian (EA) adults (median age 50 y) were reported to have higher Fe stores compared to other populations despite lacking the mutation that causes Fe overload in Northern European (NE) adults. It is unknown if these differences are evident in a healthy population under 50 y of age.

This cross-sectional study aims to compare Fe-related markers in young adults of EA and NE ancestry and identify determinants of Fe status.

Participants were healthy United States males and premenopausal/nonpregnant females of genetically confirmed EA (n = 251) or NE (n = 253) ancestry, aged 18-50 y and without obesity. A complete blood count was obtained. Serum ferritin (SF; μg/L), c-reactive protein, and interleukin-6 were measured by immunoassay, and serum soluble transferrin receptor (mg/L) and transferrin by quantitative immunoturbidimetry. Total body Fe (mg/kg) was calculated. Elevated Fe stores were defined as SF >200 (females) or >300 (males) and c-reactive protein <5 mg/L. Results are shown as the geometric mean 95% confidence interval (CI) or mean ± standard deviation.

The mean age of the population was (26.3 y; 25.6, 26.9 y), with 69.2% of participants aged under 30 y. SF was higher in EA (172; 152, 194) compared with NE (85.3; 76.8, 94.8) males (P < 0.001), and in EA (42.6; 36.7, 49.5) compared with NE (31.9; 27.8, 36.5) females (P = 0.004). The prevalence of elevated Fe stores was 16.7% in EA compared with 0.8% in NE males (P < 0.001) and 1.6% in EA compared with 0% in NE females (P = 0.47). Total body Fe was higher in EA (11.7 ± 2.7) compared with NE (9.1 ± 2.6) males (P < 0.001) and in EA (6.7 ± 3.6) compared with NE (5.6 ± 3.4) females (P = 0.01). All differences persisted after adjustment for confounders (all P < 0.05).

Individuals of EA ancestry had a significantly greater body Fe burden compared to NE individuals. Of concern, these differences were evident in a cohort primarily consisting of young individuals aged 18-29 y. This trial was registered at clinicaltrials.gov as NCT04198545.

Ferrous ions (Fe2+), the primary form of iron in cells, play a crucial role in various biological processes. The presence and absorption of Fe2+ in food has an important impact on human health. Proper dietary intake and iron supplementation are conducive to prevent and treat iron-related diseases. Therefore, it is of great value to develop tools that can specifically and sensitively detect Fe2+ in foods and organisms. Near-infrared (NIR) fluorescent probes have attracted much attention due to their advantages including deep tissue penetration and lower background fluorescence. Herein, a NIR fluorescent probe DICO-Fe(II) with a new recognition mechanism was constructed. DICO-Fe(II) achieves the highly specific recognition of Fe2+ through its carbamoyl oxime recognition site and exhibits high sensitivity with a limit of detection of 47 nM. DICO-Fe(II) can quantitatively detect Fe2+ with the naked eye through RGB values. It was also successfully applied to detect Fe2+ in food samples, cells, zebrafish, and mice tissues, confirming its potential as a modern analytical tool for the detection of Fe2+ in food and biological organisms.

One of the most common diseases worldwide is anemia, which is characterized by insufficient erythrocyte production. Numerous complex factors, such as chronic diseases, genetic mutations, and nutritional inadequacies, contribute to this widespread syndrome. This review focuses specifically on anemias caused by defective hepcidin production. Hepcidin, a peptide hormone produced primarily by liver cells, plays a crucial role in regulating iron levels by controlling its absorption. Hepcidin's mechanism of action involves binding to the ferroportin iron transporter, causing its internalization. Disturbances in iron metabolism can have far-reaching consequences, affecting not only the blood but also organs like the liver, kidneys, and brain. Iron homeostasis is crucial for maintaining optimal physiological function. Several blood-based markers are employed to assess iron stores. However, these markers have inherent limitations. Hepcidin, a key regulator of iron metabolism, plays a pivotal role in preventing iron release into the plasma from absorptive enterocytes and macrophages. Elucidating the structure and function of hepcidin is essential for understanding its role in iron homeostasis, which has significant implications for the diagnosis and management of various anemia subtypes. A well-established correlation exists between hepcidin dysregulation and iron deficiency. Despite its potential as a biomarker, the clinical application of hepcidin is hindered by the lack of a commercially available, clinically validated assay. This review aims to provide a comprehensive overview of hepcidin's role in regulating blood iron concentrations and elucidate its implications in the pathogenesis of various anemia subtypes, paving the way for its future applications in research and clinical practice.

Individuals of East Asian (EA) ancestry have greater risk of elevated iron (Fe) stores compared with individuals of Northern European (NE) ancestry, but no studies have assessed differences in Fe regulatory hormones between these populations.

This study aimed to evaluate hepcidin, erythropoietin, and erythroferrone as a function of ancestry and examine their associations with Fe status markers in United States adults of genetically confirmed EA or NE ancestry.

Participants in this cross-sectional study were healthy EA (n = 251) or NE (n = 253) males and premenopausal, nonpregnant females, aged 18-50 y, and without obesity. Serum hepcidin, erythropoietin, and erythroferrone concentrations were measured using ELISAs. Fe status [serum ferritin (SF), soluble transferrin receptor, total body iron, and transferrin], hematologic (complete blood count), and inflammatory (C-reactive protein and IL-6) markers were measured. Results are shown as the geometric mean (95% CI).

Hepcidin (ng/mL) was significantly higher in EA (43.9; 95% CI: 39.6, 48.7) compared with NE (31.3; 95% CI: 28.4, 34.5) males (P < 0.001) but did not differ between EA (21.8; 95% CI: 19.4, 24.6) and NE (21.3; 95% CI: 19.0, 23.8) females (P = 0.66). Interestingly, the hepcidin:SF ratio was lower in EA males (0.26; 95% CI: 0.23, 0.28) and females (0.51; 95% CI: 0.46, 0.57) compared with NE males (0.37; 95% CI: 0.33, 0.40; P < 0.001) and females (0.65; 95% CI: 0.57, 0.73; P = 0.01), respectively. These differences remained significant after adjustment for C-reactive protein (males: P-adjusted < 0.001; females: P-adjusted = 0.008) or IL-6 (males: P-adjusted < 0.001; females: P-adjusted = 0.006). Erythropoietin did not differ between ancestry groups in males (P = 0.11) or females (P = 0.96). Lastly, erythroferrone (ng/mL) was higher in EA (1.3; 95% CI: 0.8, 1.9) compared with NE (0.6; 95% CI: 0.4, 0.9; P = 0.009) males but did not differ between females (EA: 0.7; 95% CI: 0.5, 1.1; NE: 0.5; 95% CI: 0.3, 0.7; P = 0.11).

A lower hepcidin:SF ratio in EA compared with NE participants suggests that among EAs, hepcidin concentrations are lower relative to the load of Fe present. Further studies are needed to elucidate the mechanisms underlying the observed differences. This study was registered at clinicaltrials.gov as NCT04198545.

The SNP rs855791 has been linked to increased hepcidin levels, variations in serum iron, transferrin saturation and red blood cell indices. Our goal was to determine the prevalence of this polymorphism among COPD patients and to assess its impact on iron status parameters in patients with stable COPD.

We analysed iron status parameters and genetic data from 29 COPD patients with wild-type genotype (WT group) and 65 COPD patients with either homozygous or heterozygous genotype (HH group). Additionally, the prevalence of SNP rs855791 was assessed in 192 volunteers.

The frequency distribution of SNP rs855791 was comparable between the COPD patients and control subjects (p=0.791). Iron status parameters were within their respective reference values and showed neither statistically nor clinically significant difference between the WT and HH group of COPD patients. However, after excluding patients with (sub)clinical vitamin B12 deficiency and/or hypoxemia, WT group of patients exhibited significantly lower erythropoietin levels (p=0.015). The area under the curve for erythropoietin was 0.688 (95% CI: 0.545-0.830, p=0.015), with an optimal cut-off of 9.74, sensitivity of 61.2% (95% CI: 58.1-64.3) and specificity of 65.0% (95% CI: 61.8-68.3).

Iron status parameters do not differ between WT and HH groups of stable COPD patients. Statistical but not clinical difference in EPO levels was observed in a subgroup of patients. In addition to promoting erythropoiesis, EPO may regulate hepcidin levels and thus influence the development of iron deficiency and/or anaemia. Also, EPO's direct effect on immune cells and down-regulation of inflammatory reactions should be considered in this context.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions.

Hematological analysis is crucial for diagnosing and monitoring blood-related disorders. Nevertheless, conventional hematology analyzers remain confined to laboratory settings due to their high cost, substantial space requirements, and maintenance needs. Herein, we present a portable cell tracking velocimetry (CTV) device for the precise measurement of the magnetic susceptibility of biological entities at the single-cell level, focusing on red blood cells (RBCs) in this work. The system integrates a microfluidic channel positioned between permanent magnets that generate a well-defined magnetic field gradient (191.82 TA/mm2). When the cells are injected into the chamber, their particular response to the magnetic field is recorded and used to estimate their properties and quantify their intracellular hemoglobin (Hb) concentration. We successfully track over 400 RBCs per condition using imaging and trajectory analysis, enabling detailed characterizations of their physical and magnetic properties. A comparison of the mean corpuscular hemoglobin measurements revealed a strong correlation between our CTV system and standard ultraviolet-visible (UV-Vis) spectrophotometry (23.1 ± 5.8 pg vs. 22.4 ± 3.9 pg, p > 0.05), validating the accuracy of our measurements. The system's single-cell resolution reveals population distributions unobtainable through conventional bulk analysis methods. Thus, this portable CTV technology provides a rapid, label-free approach for magnetic cell characterization, offering new possibilities for point-of-care hematological analysis and field-based research applications.

To investigate the mechanism by which Biejiajian Pill (BJJP) regulates ferroptosis in hepatocellular carcinoma (HCC) cells through the p62/Keap1/NRF2 pathway and to provide an experimental basis for its application in the prevention and treatment of HCC.

Huh7 HCC cells were divided into a normal control group, a BJJP drug serum group, an erastin (a ferroptosis inducer) group, a BJJP drug serum + erastin group, and BJJP drug serum + ferrostatin-1 (Fer-1) (a ferroptosis inhibitor) group. BJJP drug serum was prepared with animals treated with BJJP and CCK-8 assay was performed to determine the optimal concentration and duration of BJJP intervention. The levels of intracellular iron (Fe), reduced glutathione (GSH), lipid peroxides (MDA), and reactive oxygen species (ROS) were measured. Western blot was performed to determine the expression levels of FTH1, GPX4, xCT, SLC40A1, Keapl, p62, and NRF2. JC-1 staining was performed to measure mitochondrial membrane potential, and cell immunofluorescence was performed to determine the expression of p62 and Keap1.

According to the CCK-8 assay results, the cell inhibition rate was highest when BJJP was administered at a high dose of 2.2 g/kg (P < 0.001). Furthermore, the inhibition rate of Huh7 cells was highest when Huh7 cells were treated with high-dose BJJP drug serum for 48 h. Therefore, the serum concentration of high-dose BJJP and 48 h were selected as the treatment dose and duration for the subsequent experiment. Compared with the control group, the BJJP drug serum group, the erastin group, and the BJJP drug serum + erastin group showed increased iron content, decreased GSH content, increased MDA levels, increased ROS aggregation, decreased FTH1, GPX4, xCT, SLC40A1, p62, and NRF2 contents, increased Keap1 content, and decreased mitochondrial membrane potential (P < 0.05).

BJJP regulates ferroptosis in Huh7 HCC cells by inhibiting the p62/Keap1/NRF2 pathway, demonstrating potentials as a therapeutic agent for HCC.

Hepsin (HPN), a Type II transmembrane serine protease (TTSP), is involved in hepatocyte metabolism and various diseases. It undergoes autoactivation on the surface of human hepatoma cells, a mechanism not observed in other cell types. This study aims to explore HPN activation and surface expression in endometrial epithelial cells.

We studied HPN zymogen activation and cell surface expression in human embryonic kidney 293 and endometrial epithelial AN3CA and Ishikawa cells using site-directed mutagenesis, Western blotting, flow cytometry, and immunostaining. Treatments with brefeldin A (BFA) and monensin, along with co-transfection assays, were employed to assess HPN activation and expression before reaching the cell surface. We also analyzed the activation and expression of TMPRSS2 and TMPRSS13 and examined the effect of the serine protease inhibitor HAI-1 on these proteases.

HPN zymogen autoactivates in the endoplasmic reticulum (ER) and Golgi apparatus. Its active form reduces cell surface expression through trans-autodegradation, a mechanism also applicable to in TMPRSS2 and TMPRSS13. Additionally, HAI-1 interacts with these TTSPs in different ways: it inhibits HPN activation and stabilizes its cell-surface expression; it inhibits TMPRSS2 activation without affecting its cell-surface expression; and it facilitates TMPRSS13 activation, protecting it from degradation and stabilizing its cell surface expression.

These results revealed an intracellular autoactivation and expression mechanism of HPN, TMPRSS2, and TMPRSS13, differing from the extracellular activated TTSPs. These findings provide new insights into the diverse mechanisms in regulating TTSP activation, potentially aiding in treating TTSP-related endometrial diseases.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of B-cell non-Hodgkin's lymphoma (NHL), up to 30%-40% of patients will relapse and 10%-15% of patients have primary refractory disease, so exploring new treatment options is necessary. Ferroptosis is a non-apoptotic cell death mode discovered in recent years. Its occurrence pathway plays an essential impact on the therapeutic effect of tumors. Numerous studies have shown that modulating critical factors in the ferroptosis pathway can influence the growth of tumor cells in hematological malignancies including DLBCL. This review highlights recent advances in ferroptosis-related genes (FRGs), including STAT3, Nrf2, and ZEB1, and focuses on the clinical potential of ferroptosis inducers such as IKE, α-KG, DMF, and APR-246, which are currently being explored in clinical studies for their therapeutic effects in DLBCL. Correlational studies provide a novel idea for the research and treatment of ferroptosis in DLBCL and other hematological malignancies and lay a solid foundation for future studies.

Non-alcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver disease worldwide. There are conflicting reports on the association of serum ferritin levels and its utility in discriminating various stages of liver fibrosis in patients with NAFLD. This study is done to address the conflicts by analysing the National Health and Nutritional Examination Survey 2017-2020 (NHANES 2017-2020) data. The survey data was screened, and the eligible participants (n = 5901) were categorized based on the controlled attenuation parameter (CAP) obtained from Vibration Controlled and Transient Elastography (VCTE) scan into 2 groups, NAFLD (CAP ≥ 274 dB/m, n = 2528) and non-NAFLD (CAP < 274 dB/m, n = 3373). The NAFLD group had a significantly higher proportion of obese, diabetic, and metabolic syndrome participants. Serum ferritin levels were significantly higher in the NAFLD group, and the levels showed an upward trend from simple steatosis to significant fibrosis. Multivariate regression analysis showed that ferritin has a significant positive association with the median liver stiffness parameter (LSM), which is the index of liver fibrosis. Receiver operator characteristic curve (ROC) analysis showed that serum ferritin levels are a poor predictor of fibrosis (LSM > 8 kPA) in those with NAFLD (AUC = 0.59, Sensitivity = 53.5%, Specificity = 60.3%). To conclude, serum ferritin levels were positively associated and it trended upward as the disease progressed from simple steatosis to fibrosis in NAFLD. However, its diagnostic utility in discriminating liver fibrosis in patients with NAFLD is limited.

The online version contains supplementary material available at 10.1007/s12291-023-01159-8.

Emerging research has suggested a potential link between high iron levels, indicated by serum ferritin levels, and the development of type 2 diabetes (T2D). However, the role of hepatic iron concentration (HIC) on T2D development and progression is not well understood.

This study aims to systematically review the literature on HIC and/or the degree of hepatic iron overload (HIO) in individuals with prediabetes and/or diagnosed T2D, and to analyze associations between HIC and markers of glucose metabolism.

The databases Medline, PubMed, Embase, CINAHL, and Web of Knowledge were searched for studies published in English from 1999 to March 2024. This review followed the Preferred Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.

Data were extracted following the established eligibility criteria. Study characteristics and biomarkers related to prediabetes, T2D, and HIO were extracted. The risk of bias was analyzed using the Newcastle-Ottawa Scale. Data were stratified by the exposure and analyzed in subgroups according to the outcome. Data regarding the HIC values in controls, individuals with prediabetes, and individuals with T2D and the association estimates between HIC or HIO and markers of glycemic metabolism, prediabetes, or T2D were extracted.

A total of 12 studies were identified, and data from 4110 individuals were analyzed. HIO was not consistently observed in prediabetic/T2D populations; however, elevated HIC was frequently observed in prediabetic and T2D individuals, and was associated with the disruption of certain glycemic markers in some cases.

The extent of iron overload, as indicated by hepatic iron load, varied among the prediabetic and T2D populations studied. Further research is needed to understand the distribution and regulation of iron in T2D pathology.

In low-risk myelodysplastic syndromes (MDS), the proinflammatory signaling is excessive, and the proliferation and differentiation potentials of mesenchymal stromal cells (MSCs) are strongly impaired. Eltrombopag (ELT) has been demonstrated recently effective and relatively safe in low-risk MDS with severe thrombocytopenia. However, its impact on the MDS-MSCs has not been investigated in any detail. Here, for the first time, we investigated the changes induced by ELT in MSCs' viability, proliferation, apoptosis, senescence, multilineage differentiation properties, and stem cell support capacity in low-risk MDS patients. We demonstrated that ELT may act on improving the impaired inflammatory profile and reactivating the downregulated canonical WNT signaling pathway in low-risk MDS, and also restoring the self-renewal capacity and the balance in adipose-osteogenic differentiation of MDS-MSCs.

Despite significant advancements in the research of the pathogenesis mechanisms of Myelodysplastic Neoplasm (MDS) in recent years, there are still many gaps to fill. The advancement of metabolomics studies has led to a research booming in clarifying the impact of metabolic abnormalities during the pathogenesis of MDS. The present review primarily focuses on the dysregulated metabolic pathways, exploring the influences on the pathogenesis of MDS and their roles during the course of the disease. Furthermore, we discuss the potential of relevant metabolic pathways as therapeutic targets, along with the latest metabolic-related treatment drugs and approaches.

Besides transfusion therapy, ineffective erythropoiesis contributes to systemic iron overload in myelodysplastic syndromes with ring sideroblasts (MDS-RS) via erythroferrone-induced suppression of hepcidin synthesis in the liver, leading to increased intestinal iron absorption. The underlying pathophysiology of MDS-RS, characterized by disturbed heme synthesis and mitochondrial iron accumulation, is less well understood. Several lines of evidence indicate that the mitochondrial transporter ABCB7 is critically involved. ABCB7 is misspliced and underexpressed in MDS-RS, due to somatic mutations in the splicing factor SF3B1. The pathogenetic significance of ABCB7 seems related to its role in stabilizing ferrochelatase, the enzyme incorporating iron into protoporphyrin IX to make heme. Although iron-related oxidative stress is toxic, many patients with MDS do not live long enough to develop clinical complications of iron overload. Furthermore, it is difficult to determine the extent to which iron overload contributes to morbidity and mortality in older patients with MDS, because iron-related complications overlap with age-related medical problems. Nevertheless, high-quality registry studies showed that transfusion dependency is associated with the presence of toxic iron species and inferior survival and confirmed a significant survival benefit of iron chelation therapy. The most widely used iron chelator in patients with MDS is deferasirox, owing to its effectiveness and convenient oral administration. Luspatercept, which can reduce SMAD2/SMAD3-dependent signaling implicated in suppression of erythropoiesis, may obviate the need for red blood cell transfusion in MDS-RS for more than a year, thereby diminishing further iron loading. However, luspatercept cannot be expected to substantially reduce the existing iron overload.

The term hemochromatosis refers to a group of genetic disorders characterized by hepcidin insufficiency in the context of normal erythropoiesis, iron hyperabsorption, and expansion of the plasma iron pool with increased transferrin saturation, the diagnostic hallmark of the disease. This results in the formation of toxic non-transferrin-bound iron, which ultimately accumulates in multiple organs, including the liver, heart, endocrine glands, and joints. The most common form is HFE-hemochromatosis (HFE-H) due to p.Cys282Tyr (C282Y) homozygosity, present in nearly 1 in 200 people of Northern European descent but characterized by low penetrance, particularly in females. Genetic and lifestyle cofactors (especially alcohol and dysmetabolic features) significantly modulate clinical expression so that HFE-H can be considered a multifactorial disease. Nowadays, HFE-H is mostly diagnosed before organ damage and is easily treated by phlebotomy, with an excellent prognosis. After iron depletion, maintenance phlebotomy can be usefully transformed into a blood donation program. Lifestyle changes are important for management. Non-HFE-H, much rarer but highly penetrant, may lead to early and severe heart, liver, and endocrine complications. Managing severe hemochromatosis requires a comprehensive approach optimally provided by consultation with specialized centers. In clinical practice, a proper diagnostic approach is paramount for patients referred for hyperferritinemia, a frequent finding that reflects hemochromatosis only in a minority of cases.

Hepcidin, an endogenous peptide hormone, binds to ferroportin and is the master regulator of iron trafficking. Rusfertide, a synthetic peptide, is a potent hepcidin mimetic. Clinical studies suggest rusfertide may be effective in the treatment of polycythemia vera. This study investigated the dose-ranging pharmacokinetics, pharmacodynamics, and safety of a lyophilized formulation of rusfertide.

A randomized open-label crossover study was conducted in two groups of healthy adult subjects to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous rusfertide doses that ranged from 10 to 60 mg of a lyophilized formulation and 20 mg of an aqueous prefilled syringe formulation that were used in clinical trials.

Rusfertide showed a rapid initial absorption. Median time to peak plasma concentrations for the lyophilized formulation was 24 h for doses of 10-30 mg and 2-4 h for doses of 45 and 60 mg. Mean terminal half-life ranged from 19.6 to 57.1 h. Rusfertide peak concentration and area under the concentration-time curve increased with an increasing dose, but in a less than dose-proportional manner. Metabolites M4 and M9 were identified as major metabolites. At the rusfertide 20-mg dose, the lyophilized formulation had an area under the concentration-time curve from time zero to infinity approximately 1.5-fold higher than the aqueous formulation. The elimination half-life was comparable for the two formulations. Dose-related decreases in serum iron and transferrin-iron saturation were seen following rusfertide treatment. The majority of treatment-emergent adverse events were mild; treatment-related treatment-emergent adverse events seen in ≥10% of subjects were injection-site erythema and injection-site pruritus.

Rusfertide was well tolerated; the pharmacokinetic and pharmacodynamic results indicate that lyophilized rusfertide is suitable for once-weekly or twice-weekly administration.

Black soldier fly (BSF) larvae convert wastes into protein, playing a vital role in addressing the challenge of sustainable poultry production. These larvae accumulate toxic substances, posing a risk to feed and food safety. This study investigates the effects of substituting soybean meal with different levels of BSF larvae meal on laying performance, egg quality, serum analysis, and the deposition of various metals in eggs, meat, and excreta. A total of 1,008 Lohmann hens (age 48 wk) were randomly assigned to 4 treatments. The treatments consisted of corn-soybean meal (CK) diet replaced with 7% (BSF7), 14% (BSF14), and 21% (BSF21) BSF larvae meal. Each treatment consisted of 6 replicates with 42 hens each and the trial lasted for 8 wk. Dietary BSF larvae meal treatments increased (linear, P < 0.05) the laying rate (1.52 to 1.95%) and decreased (linear, P < 0.01) the feed intake (3.64-3.86 g) during the entire experiment. During 48 to 52 wk, egg weight was decreased (P < 0.001) 0.93 g for the BSF21 group compared to CK group, however, during 52-56 wk, no differences in egg weight were observed among treatments. The addition of BSF larvae meal enhanced the eggshell strength (linear, P < 0.05), with no effect on the albumen height and yolk weight (P > 0.05). Low transfer of arsenic, lead, and cadmium concentration was observed in the egg yolk and egg white across different treatments (P > 0.05). Conversely, the concentrations of these metals and iron showed an increase, while Zinc exhibited a decrease in excreta as the dietary intake of BSF larvae meal increased. The chromium and iron increased linearly (P < 0.001) in the egg white with the inclusion of BSF larvae meal. Egg white iron and chromium showed a strong positive correlation with the dietary zinc and copper. Taken together, BSF larvae can replace soybean meal completely in laying diet, however, careful attention requires to elevated metal levels in diet and excreta.

Objectives: Hepcidin is a biomarker produced by hepatocytes in chronic disease anemia and is known to increase during chronic inflammation. This study compares the hepcidin levels in idiopathic pulmonary fibrosis (IPF) patients and controls, evaluating its relationship with anemia and systemic inflammation in IPF patients. Methods: This study included 82 IPF patients and 31 controls. Hepcidin levels were compared between the two groups. In the IPF group, the hepcidin and anemia parameters were compared between anemic and non-anemic patients. The significance between the hepcidin and systemic inflammation parameters such as Erythrocyte Sedimentation Rate, CRP (C-reactive protein) levels, ferritin levels, and the Systemic Immune-Inflammation Index (SII) was investigated. Erythrocyte Sedimentation Rate, C-reactive protein (CRP) levels, and ferritin levels were measured using automated analyzers. Hepcidin and erythropoietin (EPO) levels were determined using ELISA kits. Results: A significant difference in hepcidin levels was found between the IPF and control groups (37.13 ± 14.92 vs. 25.77 ± 11.25, p < 0.001). No significant difference in hepcidin levels was found between anemic and non-anemic IPF patients (38.25 ± 16.2 vs. 36.7 ± 14.6, p = 0.719). No significant correlation was found between hepcidin levels and anemia parameters (serum iron, ferritin, vitamin B12, serum transferrin, transferrin saturation, total iron-binding capacity, hemoglobin, folate, and erythropoietin) in IPF patients. Despite significant differences in the systemic inflammation parameters (ferritin and CRP) between patients and controls, no significant correlation was found between their hepcidin and systemic inflammation parameters. Conclusions: Our study demonstrates that the hepcidin levels in IPF patients are elevated independently of anemia and systemic inflammation. We propose that hepcidin could be a potential biomarker to be investigated in IPF patients.

The use of metal nanoparticles such as cerium oxide nanoparticles (nanoceria) in living organisms is attracting increasing attention. We administered nanoceria to chronic kidney disease model rats, including a 5/6 nephrectomy model and adenine administration model rats, and reported high phosphorus adsorption capacity and renal function improvement effects of nanoceria. However, the iron ion concentration in the serum fluctuated significantly after administration. Therefore, we investigated changes in proteins related to iron metabolism following administration of nanoceria to normal mice without chronic kidney disease over different periods of time. Nanoceria were administered to 10-week-old C57BL/6 mice for 4 or 12 weeks. Another group was administrated lanthanum carbonate, which is currently used as a phosphorus adsorbent. The amount of iron in the serum and the concentration of transferrin in the liver were significantly increased following nanoceria administration, and the amount of iron in the liver was significantly decreased. There were no changes in serum hepcidin, ferroportin, cholesterol, or low-density lipoprotein levels. These results indicate that nanoceria administration can affect iron metabolism in mice. Although the detailed mechanism remains unknown, caution is warranted when considering biological utilization in the future.

Iron deficiency is a widespread global health concern with varying prevalence rates across different regions. In developing countries, scarcity of food and chronic infections contribute to iron deficiency, while in industrialized nations, reduced food intake and dietary preferences affect iron status. Other causes that can lead to iron deficiency are conditions and diseases that result in reduced intestinal iron absorption and blood loss. In addition, iron absorption and its bioavailability are influenced by the composition of the diet. Individuals with increased iron needs, including infants, adolescents, and athletes, are particularly vulnerable to deficiency. Severe iron deficiency can lead to anemia with performance intolerance or shortness of breath. In addition, even without anemia, iron deficiency leads to mental and physical fatigue, which points to the fundamental biological importance of iron, especially in mitochondrial function and the respiratory chain. Standard oral iron supplementation often results in gastrointestinal side effects and poor compliance. Low-dose iron therapy seems to be a valid and reasonable therapeutic option due to reduced hepatic hepcidin formation, facilitating efficient iron resorption, replenishment of iron storage, and causing significantly fewer side effects. Elevated iron levels influence gut microbiota composition, favoring pathogenic bacteria and potentially disrupting metabolic and immune functions. Protective bacteria, such as bifidobacteria and lactobacilli, are particularly susceptible to increased iron levels. Dysbiosis resulting from iron supplementation may contribute to gastrointestinal disorders, inflammatory bowel disease, and metabolic disturbances. Furthermore, gut microbiota alterations have been linked to mental health issues. Future iron therapy should consider low-dose supplementation to mitigate adverse effects and the impact on the gut microbiome. A comprehensive understanding of the interplay between iron intake, gut microbiota, and human health is crucial for optimizing therapeutic approaches and minimizing potential risks associated with iron supplementation.

Estrogen-related receptor gamma (ERRγ) is a member of the ERR orphan nuclear receptor family which possesses three subtypes, α, β, and γ. ERRγ is reportedly predominantly expressed in metabolically active tissues and cells, which promotes positive and negative effects in different tissues. ERRγ overexpression in the liver, pancreas, and thyroid cells is related to liver cancer, oxidative stress, reactive oxygen species (ROS) regulation, and carcinoma. Reduced ERRγ expression in the brain, immune cells, tumor cells, and energy metabolism causes neurological dysfunction, gastric cancer, and obesity. ERRγ is a constitutive receptor; however, its transcriptional activity also depends on co-regulators, agonists, and antagonists, which, when after forming a complex, can play a role in targeting and treating diseases. Moreover, ERRγ has proven crucial in regulating cellular and metabolic activity. However, many functions mediated via ERRγ remain unknown and require further exploration. Hence, considering the importance of ERRγ, this review focuses on the critical findings and interactions between ERRγ and co-regulators, agonists, and antagonists alongside its relationship with downstream and upstream signaling pathways and diseases. This review highlights new findings and provides a path to understanding the current ideas and future studies on ERRγ-mediated cellular activity.

Metals in living organisms and environments are essential for key biological functions such as enzymatic activity, and DNA and RNA synthesis. This means that disruption of metal ion homeostasis and exchange between cells can lead to diseases. EVs are believed to play an essential role in transporting metals between cells, but the mechanism of metal packaging and exchange remains to be elucidated. Here, we established the elemental composition of EVs at the nanoscale and single-vesicle level and showed that the metal content depends on the cell type and culture microenvironment. We also demonstrated that EVs participate in the exchange of metal elements between cells. Specifically, we used two classes of EVs derived from papaya fermented fluid (PaEVs), and decidual mesenchymal stem/stromal cells (DEVs). To show that EVs transfer metal elements to cells, we treated human osteoblast-like cells (MG63) and bone marrow mesenchymal stem cells (BMMSCs) with both classes of EVs. We found that both classes of EVs contained various metal elements, such as Ca, P, Mg, Fe, Na, Zn, and K, originating from their parent cells, but their relative concentrations did not mirror the ones found in the parent cells. Single-particle analysis of P, Ca, and Fe in DEVs and PaEVs revealed varying element masses. Assuming spherical geometry, the mean mass of P was converted to a mean size of 62 nm in DEVs and 24 nm in PaEVs, while the mean sizes of Ca and Fe in DEVs were smaller, converting to 20 nm and 30 nm respectively. When EVs interacted with BMMSCs and MG63, DEVs increased Ca, P, and Fe concentrations in BMMSCs and increased Fe concentration in MG63, while PaEVs increased Ca concentrations in BMMSCs and had no effect on MG63. The EV cargo, including proteins, nucleic acids, and lipids, differs from their origin in composition, and this variation extends to the element composition of EVs in our study. This fundamental understanding of EV-mediated metal exchange between cells could offer a new way of assessing EV functionality by measuring their elemental composition. Additionally, it will contribute novel insights into the mechanisms underlying EV production and their biological activity.

gp130 functions as a shared signal-transducing subunit not only for interleukin (IL)-6 but also for eight other human cytokine receptor complexes. The IL-6 signaling pathway mediated through gp130 encompasses classical, trans, or cluster signaling, intricately regulated by a diverse array of modulators affecting IL-6, its receptor, and gp130. Currently, only a limited number of small molecule antagonists and agonists for gp130 are known. This review aims to comprehensively examine the current knowledge of these modulators and provide insights into their pharmacological properties, particularly in the context of cancer and other diseases. Notably, the prominent gp130 modulators SC144, bazedoxifene, and raloxifene are discussed in detail, with a specific focus on the discovery of SC144's iron-chelating properties. This adds a new dimension to the understanding of its pharmacological effects and therapeutic potential in conditions where iron homeostasis is significant. Our bioinformatic analysis of gp130 and genes related to iron homeostasis reveals insightful correlations, implicating the role of iron in the gp130 signaling pathway. Overall, this review contributes to the evolving understanding of gp130 modulation and its potential therapeutic applications in various disease contexts. SIGNIFICANCE STATEMENT: This perspective provides a timely and comprehensive analysis of advancements in gp130 signaling research, emphasizing the therapeutic implications of the currently available modulators. Bioinformatic analysis demonstrates potential interplay between gp130 and genes that regulate iron homeostasis, suggesting new therapeutic avenues. By combining original research findings with a broader discussion of gp130's therapeutic potential, this perspective significantly contributes to the field.

Significance: This study innovates by systematically integrating the molecular mechanisms of iron death and its application in cancer therapy. By deeply analyzing the interaction between iron death and the tumor microenvironment, the study provides a new theoretical basis for cancer treatment and directions for developing more effective treatment strategies. In addition, the study points to critical issues and barriers that need to be addressed in future research, providing valuable insights into the use of iron death in clinical translation. Recent Advances: These findings are expected to drive further advances in cancer treatment, bringing patients more treatment options and hope. Through this paper, we see the great potential of iron death in cancer treatment and look forward to more research results being translated into clinical applications in the future to contribute to the fight against cancer. Critical Issues: In today's society, cancer is still one of the major diseases threatening human health. Despite advances in existing treatments, cancer recurrence and drug resistance remain a severe problem. These problems increase the difficulty of treatment and bring a substantial physical and mental burden to patients. Therefore, finding new treatment strategies to overcome these challenges has become significant. Future Directions: The study delved into the molecular basis of iron death in tumor biology. It proposed a conceptual framework to account for the interaction of iron death with the tumor immune microenvironment, guide treatment selection, predict efficacy, explore combination therapies, and identify new therapeutic targets to overcome cancer resistance to standard treatments, peeving a path for future research and clinical translation of ferroptosis as a potential strategy in cancer therapy. Antioxid. Redox Signal. 41, 616-636. [Figure: see text].

Glyphosate and glyphosate-based herbicides (GBH), widely used globally, were initially considered harmless to humans. Experimental studies have suggested that these substances can disrupt iron homeostasis by interfering with iron uptake or triggering inflammatory responses. However, their potential impact on human iron homeostasis remains underexplored.

We analyzed data from 5812 participants aged three and older from the 2013 to 2018 NHANES. We investigated the relationships between urinary glyphosate levels, oral iron intake, and markers of iron homeostasis, including serum iron, unsaturated iron-binding capacity (UIBC), total iron-binding capacity (TIBC), transferrin saturation, ferritin, and transferrin receptor. Higher urinary glyphosate levels were positively associated with oral iron intake (β = 1.310, S.E. = 0.382, P = 0.001). A one-unit increase in the natural logarithm (ln)-glyphosate was associated with lower serum iron (β = - 4.236, 95 % CI = - 6.432 to - 2.039, P < 0.001) and ferritin (β = - 9.994, 95 % CI = - 17.342 to - 2.647, P = 0.009), and higher UIBC (β = 5.431, 95 % CI = 1.061-9.800, P = 0.018) and transferrin receptor levels (β = 0.139, 95 % CI = 0.015-0.263, P = 0.029). Increasing glyphosate exposure was associated with significant decreases in serum iron and ferritin across exposure quintiles (trend P-values = 0.003 and 0.018, respectively).

Higher glyphosate exposure is associated with reduced iron availability, suggesting potential disruptions in iron absorption. These findings underscore the need for further research into the health implications of glyphosate exposure on iron homeostasis.