Differential recovery of macrophage iron deficiency by oral iron formulations determines inflammation and autocrine hepcidin production in iron-deficiency anemia.
9 affiliations
- 1Iron Research Laboratory Lindlsey F. Kimball Research Institute, New York Blood Center New York New York United States.
- 2Department of Theoretical and Applied Sciences eCampus University Novedrate Como Italy.
- 3Department of Molecular and Translational Medicine University of Brescia Brescia Italy.
- 4Department of Pediatric Hematology/Oncology Emory University School of Medicine Atlanta Georgia United States.
- 5Aflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta Atlanta Georgia United States.
- 6Solve Sickle Cell Initiative Atlanta Georgia United States.
- 7Department of Biochemistry University of Utah Salt Lake City Utah United States.
- 8Metabolomics, Mass Spectrometry, and Proteomics Core University of Utah Salt Lake City Utah United States.
- 9Department of R&D PharmaNutra S.p.A. Pisa Italy.
Abstract
Exposure of macrophages to iron has been implicated in sterile inflammation through reactive oxygen species (ROS)-dependent cell pro-inflammatory activation. Here, we compare the effect of the commonly used oral iron salt, iron sulfate (FeSO4), with that of an innovative formulation, sucrosomial® iron (SI), on the iron status and inflammatory activation of tissue macrophages in mice with iron-deficiency (ID) anemia. Despite similar recovery of anemia and tissue ID, FeSO4 treatment, but not SI, elevated transferrin saturation, generated non-transferrin bound iron (NTBI), and quickly corrected macrophage ID compared to SI, with a more pronounced cell transferrin receptor 1 (TfR1) suppression and labile iron pool expansion. In both ex vivo and in vitro ID macrophages, the rapid kinetic of ID correction by FeSO4 was associated with increased ROS and inflammatory cytokine production, whereas these responses were minimally affected by the slower kinetic of SI uptake. Metabolome data suggest that FeSO4 but not SI suppressed lipid metabolism in macrophages, indicating reduced fatty acid β-oxidation and limited reliance on mitochondrial activity, metabolic hallmarks of cell inflammatory skewing. Ultimately, we demonstrate that FeSO4 drives a higher autocrine production of hepcidin compared to SI, via inflammatory cytokine-mediated activation of the STAT3 signaling pathway, further limiting macrophage iron recycling in ID. In conclusion, our data prove that the kinetic of macrophage ID correction by iron formulations determines cell inflammatory activation and modulates hepcidin production. Overall, SI appears a superior formulation than FeSO4 due to its reduced pro-oxidant potential, inflammatory action, and hepcidin induction, with relevance for ID treatment in individuals with pre-existing inflammatory conditions.
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BibTeX
@article{antypiuk2026differential,
title = {{Differential recovery of macrophage iron deficiency by oral iron formulations determines inflammation and autocrine hepcidin production in iron-deficiency anemia.}},
author = {Ada Antypiuk and Michela Asperti and Richa Sharma and Shobana Navaneethabalakrishnan and Navdeep Jhita and Quentinn Pearce and James E Cox and Elisa Brilli and Germano Tarantino and Francesca Vinchi},
journal = {HemaSphere},
year = {2026},
month = nov,
doi = {10.1002/hem3.70521},
url = {https://europepmc.org/article/MED/42997707},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Differential recovery of macrophage iron deficiency by oral iron formulations determines inflammation and autocrine hepcidin production in iron-deficiency anemia.
AU - Ada Antypiuk
AU - Michela Asperti
AU - Richa Sharma
AU - Shobana Navaneethabalakrishnan
AU - Navdeep Jhita
AU - Quentinn Pearce
AU - James E Cox
AU - Elisa Brilli
AU - Germano Tarantino
AU - Francesca Vinchi
PY - 2026
DA - 2026/11/06
JO - HemaSphere
DO - 10.1002/hem3.70521
UR - https://europepmc.org/article/MED/42997707
AB - Exposure of macrophages to iron has been implicated in sterile inflammation through reactive oxygen species (ROS)-dependent cell pro-inflammatory activation. Here, we compare the effect of the commonly used oral iron salt, iron sulfate (FeSO4), with that of an innovative formulation, sucrosomial® iron (SI), on the iron status and inflammatory activation of tissue macrophages in mice with iron-deficiency (ID) anemia. Despite similar recovery of anemia and tissue ID, FeSO4 treatment, but not SI, elevated transferrin saturation, generated non-transferrin bound iron (NTBI), and quickly corrected macrophage ID compared to SI, with a more pronounced cell transferrin receptor 1 (TfR1) suppression and labile iron pool expansion. In both ex vivo and in vitro ID macrophages, the rapid kinetic of ID correction by FeSO4 was associated with increased ROS and inflammatory cytokine production, whereas these responses were minimally affected by the slower kinetic of SI uptake. Metabolome data suggest that FeSO4 but not SI suppressed lipid metabolism in macrophages, indicating reduced fatty acid β-oxidation and limited reliance on mitochondrial activity, metabolic hallmarks of cell inflammatory skewing. Ultimately, we demonstrate that FeSO4 drives a higher autocrine production of hepcidin compared to SI, via inflammatory cytokine-mediated activation of the STAT3 signaling pathway, further limiting macrophage iron recycling in ID. In conclusion, our data prove that the kinetic of macrophage ID correction by iron formulations determines cell inflammatory activation and modulates hepcidin production. Overall, SI appears a superior formulation than FeSO4 due to its reduced pro-oxidant potential, inflammatory action, and hepcidin induction, with relevance for ID treatment in individuals with pre-existing inflammatory conditions.
SN - 2572-9241
ER -