Iron Overload Research Articles

Chinese guidelines for the diagnosis and treatment of hereditary hemochromatosis

Hereditary hemochromatosis is an iron overload disease caused by mutations in iron-regulating genes, resulting in excessive iron deposition in organs such as the liver, heart, skin, pancreas, and gonads, leading to corresponding multi-system damage. This condition is relatively common in European and American populations, primarily caused by mutations in the HFE gene; however, it is rare in China and other Asian countries, almost exclusively due to mutations in non-HFE genes. Clinical features include unexplained chronic hepatitis or cirrhosis, accompanied by elevated serum ferritin and/or increased transferrin saturation. MRI shows iron deposition in the liver, liver biopsy reveals iron accumulation in hepatocytes, and genetic testing facilitate the diagnosis of this disease. Repeated phlebotomy is the first-line therapy for this condition. For those who cannot tolerate phlebotomy, iron chelation therapy may be used, and patients who progress to end-stage liver disease will require liver transplantation. To assist clinicians in making informed decisions on the diagnosis and treatment of hereditary hemochromatosis, the Chinese Society of Hepatology, Chinese Medical Association has invited experts from clinical medicine, molecular genetics, pathology, imaging, and methodology to systematically summarize the advancement in this field and collaboratively develop the current guidelines.

Transcriptomic analysis and validation study of key genes and the HIF‑1α/HO‑1 pathway associated with ferroptosis in neutrophilic asthma.

Ferroptosis, as a unique form of cell death caused by iron overload and lipid peroxidation, is involved in the pathogenesis of various inflammatory diseases of the airways. Inhibition of ferroptosis has become a novel strategy for reducing airway epithelial cell death and improving airway inflammation. The aim of the present study was to analyze and validate the key genes and signaling pathways associated with ferroptosis by bioinformatic methods combined with experimental analyzes in vitro and in vivo to aid the diagnosis and treatment of neutrophilic asthma. A total of 1,639 differentially expressed genes (DEGs) were identified in the transcriptome dataset. After overlapping with ferroptosis-related genes, 11 differentially expressed ferroptosis-related genes (DE-FRGs) were obtained. A new diagnostic model was constructed by these DE-FRGs from the transcriptome dataset with those from the GSE108417 dataset. The receiver operating characteristic curve analysis indicated that the area under the curve had good diagnostic performance (>0.8). As a result, four key DE-FRGs (CXCL2, HMOX1, IL-6 and SLC7A5) and biological pathway [hypoxia-inducible factor 1 (HIF-1) signaling pathway] associated with ferroptosis in neutrophilic asthma were identified by the bioinformatics analysis combined with experimental validation. The upstream regulatory network of key DE-FRGs and target drugs were predicted and the molecular docking results from screened 37 potential therapeutic drugs revealed that the 13 small-molecule drugs exhibited a higher stable binding to the primary proteins of key DE-FRGs. The results suggested that four key DE-FRGs and the HIF-1α/heme oxygenase 1 pathway associated with ferroptosis have potential as novel markers or targets for the diagnosis or treatment of neutrophilic asthma.

Fetal hemochromatosis: rare case of hepatic and extrahepatic siderosis involving thyroid on fetal MRI

BackgroundNeonatal hemochromatosis (NH) is a rare condition that is characterized by severe neonatal liver disease in association with hepatic and extrahepatic excess iron deposition (siderosis), while sparing the reticuloendothelial system. The most common cause of fetal liver injury leading to the NH phenotype (accounting for over 95% of cases) is gestational alloimmune liver disease. This condition is caused by the transfer of maternal IgG antibodies through the placenta, targeting a fetal hepatocyte antigen. Prenatal diagnosis, particularly the identification of iron overload involving both liver and thyroid, is of significant importance and can have a profound impact on patient care. To our knowledge, no case has been reported on prenatal diagnosis of iron overload involving both liver and thyroid.Case presentationWe present an exceptionally rare case of fetal hemochromatosis in a primigravida, a case that significantly contributes to our understanding of this condition. The diagnosis was made with the presence of hepatic and extrahepatic siderosis involving the thyroid using Ultrasonography (USG) and fetal Magnetic Resonance Imaging (MRI) findings. A 23-year-old primigravida was referred to our center in view of oligohydramnios, Intrauterine Growth Restriction (IUGR) and echogenic bowel at 29 weeks of gestation. USG and fetal MRI showed features of coarse liver echotexture and iron overload involving the liver and thyroid; this is the first case describing iron accumulation in the fetal thyroid gland diagnosed in utero.ConclusionThis case underscores the critical importance of performing MRI in suspected cases of fetal hemochromatosis for early diagnosis and intervention, emphasizing the potential to significantly improve patient outcomes.

Iron Overdose in Pregnant Women and its Treatment

During pregnancy, Iron requirements increase significantly to support the growth of the foetus and placenta, as well as maternal erythropoietic expansion. Iron supplementation is universally recommended for a viable pregnancy, irrespective of maternal Iron status. A food fortification strategy delivering about 10mg Iron per day lowers the proportion of women under risk of Iron deficiency to the range of 6 per cent to 39 per cent in many states. Combining fortification with weekly supplementation would lower the risk to between 1 per cent and 5 per cent. Food fortification and supplementation would expose many women to Iron levels that exceed the tolerable upper level of 45mg per day, producing Iron overload which can be prove to be toxic. Large epidemiological studies show a U-shaped association between maternal ferritin, a marker of Iron stores, and risk of adverse outcomes of pregnancy such as low birthweight, stillbirth, preterm birth (<37 weeks), very preterm birth (<32 weeks’ gestation), and neonatal asphyxia.

A clinical case of liver iron overload in a child with liver cavernoma and extrahepatic portal hypertension

A clinical case of liver iron overload in a child with liver cavernoma and extrahepatic portal hypertension

Lipid radicals and oxidized cholesteryl esters in low- and high-density lipoproteins in patients with β-thalassemia: Effects of iron overload and iron chelation therapy

Iron overload results in lipid peroxidation (LPO) and the oxidative modification of circulating lipoproteins, which contributes to cardiovascular complications in patients with β-thalassemia. Investigating LPO may provide opportunities for the development of novel therapeutic strategies; however, the chemical pathways underlying iron overload-induced LPO in β-thalassemia lipoproteins remain unclear. In this study, we identified various species of lipid radicals (L•), the key mediators of LPO, and oxidized cholesteryl esters (oxCE) derived from the in vitro oxidation of major core lipids, cholesteryl linoleate (CE18:2) and cholesteryl arachidonate (CE20:4); the levels of these radical products in low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were measured and compared between β-thalassemia patients and healthy subjects by using a specific fluorescent probe for L• with a liquid chromatography-tandem mass spectrometric method. Our results demonstrated that iron overload substantially decreased the levels of CE18:2 and CE20:4 substrates and α-tocopherol, resulting in higher levels of full-length and short-chain truncated L• and oxCE products. In particular, CE epoxyallyl radicals (•CE-O) were observed in the lipoproteins of β-thalassemia, revealing the pathological roles of iron overload in the progression of LPO. In addition, we found that intermission for two weeks of iron chelators can increase the production of these oxidized products; therefore, suggesting the beneficial effects of iron chelators in preventing LPO progression. In conclusion, our findings partly revealed the primary chemical pathway by which the LPO of circulating lipoproteins is influenced by iron overload and affected by iron chelation therapy. Moreover, we found that •CE + O shows potential as a sensitive biomarker for monitoring LPO in individuals with β-thalassemia.

Epidemiological and transcriptome data identify association between iron overload and metabolic dysfunction-associated steatotic liver disease and hepatic fibrosis

The primary objective of this study was to examine the association between iron overload (IO), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatic fibrosis. We hypothesized that there is a significant association. Data from the NHANES (2017-2020) were analyzed to explore IO's impact on MASLD and hepatic fibrosis in U.S. adults. We assessed serum ferritin, controlled attenuation parameter (CAP), liver stiffness measurement (LSM), and various covariates. Gene expression data were sourced from the FerrDb V2 and GEO databases. Differential gene expression analysis, Protein-Protein Interaction (PPI) Network construction, and Gene Ontology (GO) and KEGG pathway enrichment analyses were performed. The study verified the link between MASLD, hepatic fibrosis, and iron overload hub genes. This study of 5927 participants, averaging 46.78 years of age, revealed significant correlations between serum ferritin and CAP, LSM, after adjusting for covariates. Threshold effect analysis indicated nonlinear associations between serum ferritin and CAP, LSM, with distinct patterns observed by age and gender. Moreover, the area under the ROC curve for serum ferritin with MASLD and hepatic fibrosis was 0.8272 and 0.8376, respectively, demonstrating its performance in assessing these conditions. Additionally, molecular analyses identified potential hub genes associated with iron overload and MASLD, and hepatic fibrosis, revealing the underlying mechanisms. Our study findings reveal an association between iron overload, MASLD, and hepatic fibrosis. Additionally, the hub genes may be implicated in iron overload and subsequently contribute to the progression of MASLD and hepatic fibrosis. These findings support precision nutrition strategies.

Serum Homocysteine Levels and Their Relationship With Serum Vitamin B12, Folate, and Ferritin Levels in Transfusion-Dependent Thalassemic Children.

The purpose of this study was to assess serum homocysteine levels and their relationship with serum vitamin B12, folate, and ferritin levels in transfusion-dependent thalassemic children. This study was proposed due to a paucity of literature regarding the status of homocysteine levels in thalassemic children and their relationship with the levels of vitamins and iron overload (serum ferritin values). A descriptive observational study was conducted on transfusion-dependent thalassemic children aged 1-18 years, who were registered at the Thalassemia Day Care Centre (TDCC), Umaid Hospital, Dr. SN Medical College, Jodhpur, over a period of six months. A total of 100 children were enrolled in the study, with a mean age of 8.89±4.50 years. The mean pre-transfusion hemoglobin level in the last six months was 8.23±1.02 gm/dL. The mean serum levels of homocysteine, vitamin B12, folic acid, and ferritin were 10.93±3.72 µmol/L, 164.03±80.54 pg/mL, 7.69±5.77 ng/mL, and 2175.78±1341.39 ng/mL, respectively. A statistically significant negative correlation was detected between serum vitamin B12 concentration and serum homocysteine concentration (r=-0.285, p=0.004). Statistically non-significant positive correlations were detected between serum folic acid and serum homocysteine levels (r=0.033, p=0.748) and between serum ferritin and serum homocysteine levels (r=0.179, p=0.075). A statistically significant negative correlation between serum homocysteine and vitamin B12 levels was noted, whereas statistically non-significant positive correlations were observed between serum homocysteine andserum folic acid levels and between serum homocysteine andserum ferritin levels.

Iron Deficiency Anemia and Migraine: A Literature Review of the Prevalence, Pathophysiology, and Therapeutic Potential.

This literature review explores the association between iron deficiency anemia and migraines, examining their prevalence, underlying pathophysiology, and therapeutic potential of iron supplementation in managing migraine symptoms. A systematic search across major academic databases, including PubMed, Google Scholar, ScienceDirect, and Science.gov, identified relevant peer-reviewed studies that focus on the link between iron deficiency anemia and migraines. The review highlights a higher prevalence of iron deficiency anemia among migraine sufferers, particularly women, with several studies indicating a significant inverse relationship between serum ferritin levels and migraine severity. The findings suggest that low iron levels may exacerbate migraine symptoms, and iron supplementation has been shown to reduce the frequency and intensity of migraines, especially in patients with confirmed iron deficiency anemia. The review also discusses the unique susceptibility of women, particularly those of reproductive age, to both iron deficiency anemia and migraines, emphasizing the importance of gender-specific approaches in treatment. Moreover, the potential impact of iron deficiency on neurovascular function and its contribution to migraine pathogenesis is explored, reinforcing the need for comprehensive management strategies that include nutritional interventions. While iron supplementation appears to be a promising therapeutic option, further research is required to fully understand its long-term effects and to refine treatment protocols to avoid the risks associated with iron overload. This review underscores the significance of addressing nutritional deficiencies as part of a holistic approach to migraine management, offering insights into potential avenues for improving patient outcomes.

Iron chelation as a new therapeutic approach to prevent senescence and liver fibrosis progression

Iron overload and cellular senescence have been implicated in liver fibrosis, but their possible mechanistic connection has not been explored. To address this, we have delved into the role of iron and senescence in an experimental model of chronic liver injury, analyzing whether an iron chelator would prevent liver fibrosis by decreasing hepatocyte senescence. The model of carbon tetrachloride (CCl4) in mice was used as an experimental model of liver fibrosis. Results demonstrated that during the progression of liver fibrosis, accumulation of iron occurs, concomitant with the appearance of fibrotic areas and cells undergoing senescence. Isolated parenchymal hepatocytes from CCl4-treated mice present a gene transcriptomic signature compatible with iron accumulation and senescence, which correlates with induction of Reactive Oxygen Species (ROS)-related genes, activation of the Transforming Growth Factor-beta (TGF-β) pathway and inhibition of oxidative metabolism. Analysis of the iron-related gene signature in a published single-cell RNA-seq dataset from CCl4-treated livers showed iron accumulation correlating with senescence in other non-parenchymal liver cells. Treatment with deferiprone, an iron chelator, attenuated iron accumulation, fibrosis and senescence, concomitant with relevant changes in the senescent-associated secretome (SASP), which switched toward a more anti-inflammatory profile of cytokines. In vitro experiments in human hepatocyte HH4 cells demonstrated that iron accumulates in response to a senescence-inducing reagent, doxorubicin, being deferiprone able to prevent senescence and SASP, attenuating growth arrest and cell death. However, deferiprone did not significantly affect senescence induced by two different agents (doxorubicin and deoxycholic acid) or activation markers in human hepatic stellate LX-2 cells. Transcriptomic data from patients with different etiologies demonstrated the relevance of iron accumulation in the progression of liver chronic damage and fibrosis, correlating with a SASP-related gene signature and pivotal hallmarks of fibrotic changes. Altogether, our study establishes iron accumulation as a clinically exploitable driver to attenuate pathological senescence in hepatocytes.

Focus on the role of calcium signaling in ferroptosis: a potential therapeutic strategy for sepsis-induced acute lung injury.

By engaging in redox processes, ferroptosis plays a crucial role in sepsis-induced acute lung injury (ALI). Although iron stimulates calcium signaling through the stimulation of redox-sensitive calcium pathways, the function of calcium signals in the physiological process of ferroptosis in septic ALI remains unidentified. Iron homeostasis disequilibrium in ferroptosis is frequently accompanied by aberrant calcium signaling. Intracellular calcium overflow can be a symptom of dysregulation of the cellular redox state, which is characterized by iron overload during the early phase of ferroptosis. This can lead to disruptions in calcium homeostasis and calcium signaling. The mechanisms controlling iron homeostasis and ferroptosis are reviewed here, along with their significance in sepsis-induced acute lung injury, and the potential role of calcium signaling in these processes is clarified. We propose that the development of septic acute lung injury is a combined process involving the bidirectional interaction between iron homeostasis and calcium signaling. Our goal is to raise awareness about the pathophysiology of sepsis-induced acute lung injury and investigate the relationship between these mechanisms and ferroptosis. We also aimed to develop calcium-antagonistic therapies that target ferroptosis in septic ALI and improve the quality of survival for patients suffering from acute lung injury.

Assessment of Cardiac, Hepatic and Pancreatic Iron Overload in Transfusion Dependent Thalassemia Patients Using T2* Magnetic Resonance Imaging

Assessment of Cardiac, Hepatic and Pancreatic Iron Overload in Transfusion Dependent Thalassemia Patients Using T2* Magnetic Resonance Imaging

Study on the role of iron chelators in the management of iron overload among transfusion-dependent thalassemia (TDT) pediatric patients

This study aims to investigate the efficacy and safety of Deferasirox, an oral iron chelator, in reducing iron burden in pediatric patients with transfusion-dependent beta-thalassemia. Thalassemia syndromes, particularly beta-thalassemia, are inherited hemoglobin disorders requiring regular blood transfusions, leading to iron overload and subsequent complications. Effective management of iron overload is crucial to prevent morbidity and mortality. It was a descriptive observational study on Children between the ages of 2 years and 12 years who present with transfusion-dependent thalassemia and areon blood transfusion and develop iron overload, which is evaluated by serum ferritin levels of more than 2000mcg/l are administered iron chelator Deferasirox (14 mg/kg/d)and patients are evaluated for myocardial, hepatic, pancreatic iron burden and conditions of iron toxicity with the help of Cardiac MRI T2, LIC (Liver Iron Concentration), MRI T2 Pancreas, LVEF (Left Ventricular Ejection Fraction). A total of 22 patients enrolled in the study; significant reductions were observed in mean serum ferritin levels (2,388 mcg/dl to 2,054 mcg/dl, p=0.0009), transferrin saturation (70.45% to 64.32%, p=0.00005), and serum transaminases (44.55 U/L to 40.27 U/L, p=0.003) at 6 months. Cardiac MRI T2* increased from 19.55 ms to 22.95 ms (p=0.045) at the end of 6 months and at the end of 12 months from 19.55 to 28.23 (p=0.0016), and LIC reduced from 20.73 mg Fe/g dw to 11.59 mg Fe/g dw (p=0.00005). Pancreatic T2 improved from 15.96 ms to 20.23 ms at 12 months (p=0.007). A transient increase in serum creatinine was observed at 6 months from 0.64+/-0.14 mg/dL to 0.7+/-0.13mg/dL(p=0.009), which returned to normal at the end of 12 months to 0.63 mg/dL, no additional therapy-related adverse events were reported. Deferasirox has demonstrated significant efficacy in reducing iron overload in pediatric patients with transfusion-dependent beta thalassemia over a 12-month period. The substantial improvements in serum ferritin, cardiac MRI T2*, LIC, transferrin saturation, and pancreatic T2, coupled with its excellent safety profile, support the use of DFX as a cornerstone in the management of iron overload in this vulnerable population.

Improving Cognitive Function: Blood Transfusions and Neurological Benefits in HIV Management

HIV-associated neurocognitive disorders (HAND) continue to affect a significant number of individuals despite the widespread use of antiretroviral therapy (ART). This review explores the potential benefits of blood transfusions in improving cognitive function among HIV patients. Blood transfusions, primarily used to treat anemia, can enhance oxygen delivery to the brain, thereby ameliorating cognitive deficits. Anemia is a common comorbidity in HIV, and its correction through blood transfusions has been associated with improvements in attention, memory, and executive function. Beyond addressing anemia, blood transfusions may also offer neuroprotective effects by modulating systemic inflammation. Chronic inflammation, a hallmark of HIV infection, contributes significantly to neurocognitive decline. By reducing levels of pro-inflammatory cytokines, blood transfusions can potentially mitigate neuroinflammation and protect against neuronal damage. Clinical studies have shown that HIV patients receiving blood transfusions for anemia management exhibit slower cognitive decline, suggesting a broader role for transfusions in preserving neurological health. While promising, the use of blood transfusions in HIV management must be carefully considered due to associated risks such as transfusion reactions and iron overload. Keywords: HIV, cognitive function, blood transfusions, neurological benefits, neurocognitive disorders

Refining the Rab7-V1G1 axis to mitigate iron deposition: Protective effects of quercetin in alcoholic liver disease

Iron overload is a common feature of alcoholic liver disease (ALD) and contributes significantly to disease progression. Quercetin, a flavonoid known for its iron-chelating properties, has emerged as a potential protective compound against ALD. However, research on quercetin's regulatory effects on iron levels in ALD is limited. To address this, we conducted a study using male C57BL/6J mice were subjected to a Lieber De Carli liquid diet containing ethanol (28% energy replacement) with or without quercetin supplementation (100 mg/kg.BW) for 12 weeks. Additionally, HepG2 cells, after transfection with the CYP2E1 plasmid, were incubated with ethanol and/or quercetin. Our findings revealed that ethanol consumption led to iron overload in both hepatocytes and lysosomes. Interestingly, despite the increase in iron levels, cells exhibited impaired iron utilization, disrupting normal iron metabolism. Further analysis identified a potential mechanism involving the Rab7-V1G1 (V-ATPase subunit) axis. Inhibition of V-ATPase by Concanamycin A caused elevated ROS levels, impaired lysosomal and mitochondria function, and increased expression of HIF1α and IRP2. Ultimately, this disruption in cellular processes led to iron overload and mitochondrial iron deficiency. Quercetin supplementation mitigated ethanol-induced hepatocyte damage by reversing iron overload through modulation of the Rab7-V1G1 axis and improving the interaction between lysosomes and mitochondria. In conclusion, this study elucidates a novel pathophysiological mechanism by which quercetin protects against ALD through its regulation of iron homeostasis.

Ferroptosis in Ischemic Stroke and Related Traditional Chinese Medicines.

Stroke is a severe neurological disorder resulting from the rupture or blockage of blood vessels, leading to significant mortality and disability worldwide. Among the different types of stroke, ischemic stroke (IS) is the most prevalent, accounting for 70-80% of cases. Cell death following IS occurs through various mechanisms, including apoptosis, necrosis, and ferroptosis. Ferroptosis, a recently identified form of regulated cell death characterized by iron overload and lipid peroxidation, was first described by Dixon in 2012. Currently, the only approved pharmacological treatment for IS is recombinant tissue plasminogen activator (rt-PA), which is limited by a narrow therapeutic window and often results in suboptimal outcomes. Recent research has identified several traditional Chinese medicines (TCMs) that can inhibit ferroptosis, thereby mitigating the damage caused by IS. This review provides an overview of stroke, the role of ferroptosis in IS, and the potential of certain TCMs to inhibit ferroptosis and contribute to stroke treatment.

Iron regulatory protein two facilitates ferritinophagy and DNA damage/repair through guiding ATG9A trafficking

Trace elemental iron is an essential nutrient that participates in diverse metabolic processes. Dysregulation of cellular iron homeostasis, both iron deficiency and iron overload, is detrimental and tightly associated with diseases pathogenesis. IRPs-IREs system locates at the center for iron homeostasis regulation. Additionally, ferritinophagy, the autophagy-dependent ferritin catabolism for iron recycle, is emerging as a novel mechanism for iron homeostasis regulation. It is still unclear whether IRPs-IREs system and ferritinophagy are synergistic or redundant in determining iron homeostasis. Here we report that IRP2, but not IRP1, is indispensable for ferritinophagy in response to iron depletion. Mechanistically, IRP2 ablation results in compromised AMPK activation and defective ATG9A endosomal trafficking, leading to the decreased engulfment of NCOA4-ferritin complex by endosomes and the subsequent dysregulated endosomal microferritinophagy. Moreover, this defective endosomal microferritinophagy exacerbates DNA damage and reduces colony formation in IRP2 depleted cells. Collectively, this study expands the physiological function of IRP2 in endosomal microferritinophagy and highlights a potential crosstalk between IRPs-IREs and ferritinophagy in manipulating iron homeostasis.

Insight into myocardial ischemia-reperfusion injury from the perspective of ferroptosis.

Myocardial ischemia-reperfusion injury (MIRI) most frequently happens in acute myocardial infarction (AMI) when rapid reperfusion is utilized to save the ischemia myocardium. MIRI is the main contributing of poor healing in AMI and is related to high mortality and disability rates around the worldwide. Currently, there is no effective precautionary measure for MIRI. Ferroptosis is a novel regulated cell death characterized by iron overload and reactive oxygen species (ROS) accumulation, which lead to death membrane lipid peroxidation. An increasing amount of studies indicates that ferroptosis plays a vital role in the occurrence and progression of MIRI. Given the crucial role of ferroptosis in MIRI, it is critical to understand the cardiomyocyte iron metabolism and investigate the molecular mechanisms of ferroptosis. In this review, we systematically summarize the molecular and metabolic pathways of ferroptosis in context of MIRI, which could provide novel understandings for the pathophysiological machine and new ideas for treatment.

Spns1 is an iron transporter essential for megalin-dependent endocytosis.

Proximal tubule endocytosis is essential to produce protein-free urine as well as to regulate system-wide metabolic pathways, such as the activation of Vitamin D. We have determined that the proximal tubule expresses an endolysosomal membrane protein, protein spinster homolog1 (Spns1), which engenders a novel iron conductance that is indispensable during embryonic development. Conditional knockout of Spns1 with a novel Cre-LoxP construct specific to megalin-expressing cells led to the arrest of megalin receptor-mediated endocytosis as well as dextran pinocytosis in proximal tubules. The endocytic defect was accompanied by changes in megalin phosphorylation as well as enlargement of lysosomes, confirming previous findings in Drosophila and Zebrafish. The endocytic defect was also accompanied by iron overload in proximal tubules. Remarkably, iron levels regulated the Spns1 phenotypes because feeding an iron-deficient diet or mating Spns1 knockout with divalent metal transporter1 knockout rescued the phenotypes. Conversely, iron-loading wild-type mice reproduced the endocytic defect. These data demonstrate a reversible, negative feedback for apical endocytosis and raise the possibility that regulation of endocytosis, pinocytosis, megalin activation, and organellar size and function is nutrient-responsive.NEW & NOTEWORTHY Spns1 mediates a novel iron conductance essential during embryogenesis. Spns1 knockout leads to endocytic and lysosomal defects, accompanied by iron overload in the kidney. Reversal of iron overload by restricting dietary iron or by concurrent knockout of the iron transporter, DMT1 rescued the endocytic and organellar defects and reverted markers of iron overload. These data suggest feedback between iron and proximal tubule endocytosis.

Research progress of ferroptosis in female infertility

Ferroptosis is a novel type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides in cells and is closely related to various diseases. Female infertility is a global health concern, which is associated with a variety of factors. The etiology remains unknown in many women with infertility. With further investigation into the pathogenesis of infertility, a growing number of studies have demonstrated the close connections between infertility and ferroptosis. Through a literature review, it is found that ferroptosis is closely involved in endometriosis- and polycystic ovarian syndrome (PCOS)-associated infertility and tubal factor infertility. Iron overload increases the resistance to ferroptosis, and ferroptosis in some cells accelerates endometrial lesion growth. Moreover, iron overload may be hazardous to oocytes. This review may shed some light on the diagnosis and treatment of female infertility.