ArticlePloS one2021
Iron overload inhibits BMP/SMAD and IL-6/STAT3 signaling to hepcidin in cultured hepatocytes.
Article in PloS one, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 44 citations in OpenAlex.
- Aerobic exercise and NBS superfood supplementation modulate iron-related biomarkers in methadone treated men in randomized double blind controlled trial.Scientific reports · 2025Trial
- Activating Cannabinoid receptor 2 alleviates iron overload-induced liver damage via dual modulation of STAT3/hepcidin and Nrf2/FPN1 pathways.Molecular biomedicine · 2026Article
- Ferroportin at the Crossroads of Iron Biology: Disease, Regulation and Modulation.Biomolecules · 2026Review
- The interplay between cytokine genes and microRNAs in anemia of inflammation among hemodialysis patients.Scientific reports · 2026Article
- Review
- The iron-ferroptosis axis in bone homeostasis: a potential complementary pathway for osteoporosis in endometriosis.European journal of medical research · 2026Review
- Circulating microRNA molecular signatures converge with erythroid phenotypes and iron homeostasis in pediatric tic disorders.Frontiers in psychiatry · 2026Article
- Targeting ferroptosis as a therapeutic strategy for hepatotoxicity.Toxicology reports · 2025Review
- Article
- Ferroptosis as a key player in the pathogenesis and intervention therapy in liver injury: focusing on drug-induced hepatotoxicity.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Dietary Iron Intake and Obesity-related Diseases.Current diabetes reports · 2025Review
- HFE-Related Hemochromatosis May Be a Primary Kupffer Cell Disease.Biomedicines · 2025Review
- Defined Diets Link Iron and α-Linolenic Acid to Cyp1b1 Regulation of Neonatal Liver Development Through Srebp Forms and LncRNA H19.International journal of molecular sciences · 2025Article
- Three signalling pathways for iron overload in osteoporosis: a narrative review.Journal of orthopaedic surgery and research · 2025Review
- Recurrent BMP4 variants in exon 4 cause non-HFE-associated hemochromatosis via the BMP/SMAD signaling pathway.Orphanet journal of rare diseases · 2024Article
- Iron homeostasis and insulin sensitivity: unraveling the complex interactions.Reviews in endocrine & metabolic disorders · 2024Review
- Iron Overload Induces Hepatic Ferroptosis and Insulin Resistance by Inhibiting the Jak2/stat3/slc7a11 Signaling Pathway.Cell biochemistry and biophysics · 2024Article
- Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.Nature genetics · 2024Article
- Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure.European journal of medical research · 2024Review
- Uncovering the Cardioprotective Potential of Diacerein in Doxorubicin Cardiotoxicity: Mitigating Ferritinophagy-Mediated Ferroptosis via Upregulating NRF2/SLC7A11/GPX4 Axis.Antioxidants (Basel, Switzerland) · 2024Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Hepcidin is a peptide hormone that targets the iron exporter ferroportin, thereby limiting iron entry into the bloodstream. It is generated in hepatocytes mainly in response to increased body iron stores or inflammatory cues. Iron stimulates expression of bone morphogenetic protein 6 (BMP6) from liver sinusoidal endothelial cells, which in turn binds to BMP receptors on hepatocytes and induces the SMAD signaling cascade for transcriptional activation of the hepcidin-encoding HAMP mRNA. SMAD signaling is also essential for inflammatory HAMP mRNA induction by the IL-6/STAT3 pathway. Herein, we utilized human Huh7 hepatoma cells and primary murine hepatocytes to assess the effects of iron perturbations on signaling to hepcidin. Iron chelation appeared to slightly impair signaling to hepcidin. Subsequent iron supplementation not only failed to reverse these effects, but drastically reduced basal HAMP mRNA and inhibited HAMP mRNA induction by BMP6 and/or IL-6. Thus, treatment of cells with excess iron inhibited basal and BMP6-mediated SMAD5 phosphorylation and induction of HAMP, ID1 and SMAD7 mRNAs in a dose-dependent manner. Iron also inhibited IL-6-mediated STAT3 phosphorylation and induction of HAMP and SOCS3 mRNAs. These responses were accompanied by induction of GCLC and HMOX1 mRNAs, known markers of oxidative stress. We conclude that hepatocellular iron overload suppresses hepcidin by inhibiting the SMAD and STAT3 signaling pathways downstream of their respective ligands.
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