{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Iron Research Laboratory Lindlsey F. Kimball Research Institute, New York Blood Center New York New York United States.",
    "Department of Theoretical and Applied Sciences eCampus University Novedrate Como Italy.",
    "Department of Molecular and Translational Medicine University of Brescia Brescia Italy.",
    "Department of Pediatric Hematology/Oncology Emory University School of Medicine Atlanta Georgia United States.",
    "Aflac Cancer and Blood Disorders Center Children's Healthcare of Atlanta Atlanta Georgia United States.",
    "Solve Sickle Cell Initiative Atlanta Georgia United States.",
    "Department of Biochemistry University of Utah Salt Lake City Utah United States.",
    "Metabolomics, Mass Spectrometry, and Proteomics Core University of Utah Salt Lake City Utah United States.",
    "Department of R&D PharmaNutra S.p.A. Pisa Italy."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Ada Antypiuk",
      "orcid": "0009-0008-5498-3440"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Michela Asperti",
      "orcid": "0000-0002-7830-6494"
    },
    {
      "affs": [
        0
      ],
      "name": "Richa Sharma"
    },
    {
      "affs": [
        0
      ],
      "name": "Shobana Navaneethabalakrishnan",
      "orcid": "0000-0002-8768-4681"
    },
    {
      "affs": [
        3,
        4,
        5
      ],
      "name": "Navdeep Jhita",
      "orcid": "0000-0003-3862-0689"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Quentinn Pearce"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "James E Cox",
      "orcid": "0000-0002-5977-2350"
    },
    {
      "affs": [
        8
      ],
      "name": "Elisa Brilli",
      "orcid": "0000-0002-5053-5164"
    },
    {
      "affs": [
        8
      ],
      "name": "Germano Tarantino",
      "orcid": "0000-0001-7264-1614"
    },
    {
      "affs": [
        0,
        3,
        4,
        5
      ],
      "name": "Francesca Vinchi",
      "orcid": "0000-0003-1631-8286"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2hsw9kveeb12h.bib",
  "cited_by": 0,
  "doi": "10.1002/hem3.70521",
  "fulltext_url": "https://europepmc.org/articles/PMC13743196",
  "id": "2hsw9kveeb12h",
  "issns": [
    "2572-9241"
  ],
  "landing_url": "https://europepmc.org/article/MED/42997707",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2720|Iron Metabolism and Disorders"
    ]
  ],
  "openalex": "W7225377229",
  "pdf_url": "https://europepmc.org/articles/PMC13743196?pdf=render",
  "pmcid": "PMC13743196",
  "pmid": "42997707",
  "published": "2026-11-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2hsw9kveeb12h.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:34Z",
      "native_id": "MED:42997707",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42997707"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2720|Iron Metabolism and Disorders",
      "subfield": "general"
    }
  ],
  "title": "Differential recovery of macrophage iron deficiency by oral iron formulations determines inflammation and autocrine hepcidin production in iron-deficiency anemia.",
  "title_text": "Differential recovery of macrophage iron deficiency by oral iron formulations determines inflammation and autocrine hepcidin production in iron-deficiency anemia.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:34Z",
  "url": "https://research.draconitic.com/paper/2hsw9kveeb12h",
  "venue": "HemaSphere",
  "versions": []
}