{
  "abstract": "Systemic iron overload precipitates progressive and often irreversible organ dysfunction, yet the clinical toolkit for non-invasive, organ-specific monitoring of iron accumulation remains inadequate. This study leverages a proteome-wide causal inference framework to identify circulating biomarkers that drive or reflect iron deposition in the liver, spleen, and pancreas. We integrated large-scale plasma pQTL data (n = 35,559) with GWAS summary statistics of organ-specific iron content using two-sample Mendelian randomization (MR). Candidate proteins were prioritized through Bayesian colocalization to identify shared genetic etiologies. The findings were validated in a systemic iron-overload mouse model, assessing the concordance between genetically predicted effects and experimental protein expression, histopathology, and systemic iron markers. MR analysis identified PRSS1 as a high-confidence causal mediator and prioritized BGLAP, FTMT, and ZHX3 as candidate proteins associated with tissue iron homeostasis. Genetically predicted BGLAP levels exhibited a negative causal effect on liver iron content (β = -0.294, P = 6.35 × 10⁻⁶), while FTMT and ZHX3 were positively associated with splenic iron accumulation. Notably, PRSS1 demonstrated a robust negative association with pancreatic iron (β = -0.217, P = 1.28 × 10⁻⁵) and showed strong evidence of genetic colocalization (PP.H4 = 0.982), suggesting a direct regulatory role. These MR-prioritized protein targets exhibited directionally concordant in vivo associations with organ iron accumulation and pharmacological iron chelation in mouse models of systemic iron overload. Our study establishes a genetically anchored proteomic map of systemic iron variation, prioritizing PRSS1 alongside BGLAP, FTMT, and ZHX3 as candidate proteins associated with organ-specific iron homeostasis. Rather than providing definitive clinical tools, these findings offer hypothesis-generating insights that warrant rigorous prospective validation in clinical iron-overload patient cohorts and dedicated functional models.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "Mingwei Wang"
    },
    {
      "name": "Qiaohui Ying"
    },
    {
      "name": "Xia Lou"
    },
    {
      "name": "Qing Li"
    },
    {
      "name": "Chuang Li"
    },
    {
      "name": "Shuchang Dai"
    },
    {
      "name": "Xiaolin Du"
    },
    {
      "name": "Jue Wang"
    },
    {
      "name": "Ling Li"
    },
    {
      "name": "Zhong Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/64k3mp0bjwedd.bib",
  "cited_by": 0,
  "doi": "10.1038/s41598-026-73951-4",
  "fulltext_url": null,
  "id": "64k3mp0bjwedd",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://www.nature.com/articles/s41598-026-73951-4",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2720|Iron Metabolism and Disorders"
    ]
  ],
  "openalex": "W7223668741",
  "pdf_url": "https://www.nature.com/articles/s41598-026-73951-4_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/64k3mp0bjwedd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:34Z",
      "native_id": "10.1038/s41598-026-73951-4",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41598-026-73951-4"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2720|Iron Metabolism and Disorders",
      "subfield": "general"
    }
  ],
  "title": "Causal landscape of the circulating proteome in systemic iron overload revealed by Mendelian randomization and experimental validation",
  "title_text": "Causal landscape of the circulating proteome in systemic iron overload revealed by Mendelian randomization and experimental validation",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:34Z",
  "url": "https://research.draconitic.com/paper/64k3mp0bjwedd",
  "venue": "Scientific Reports",
  "versions": []
}