{
  "abstract": "Background: Excessive fructose consumption has become increasingly prevalent in modern diets and is strongly associated with metabolic disorders and elevated cardiovascular risk. Vascular calcification, a major contributor to arterial stiffness, is regulated by the balance between pro-calcifying factors and endogenous calcification inhibitors such as extracellular inorganic pyrophosphate. However, the effects of chronic fructose intake on pyrophosphate homeostasis, as well as their contribution to vascular calcification, remain incompletely understood.\n\nMethods: Male Sprague–Dawley rats were exposed to a 10% fructose-enriched drinking solution for three months. Metabolic, biochemical, and vascular parameters were assessed, including plasma glucose, insulin, inflammatory cytokines, uric acid, mineral metabolism markers, ATP and pyrophosphate levels, hepatic mitochondrial function, and aortic calcification. Extracellular pyrophosphate metabolism in the aortic wall was evaluated, and the effects of genetic or pharmacological dual inhibition of TNAP and eNTPD1 on vascular calcification were examined ex vivo.\n\nResults: Fructose-fed rats developed hyperglycemia, hyperinsulinemia, elevated inflammatory cytokines, and increased uric acid levels despite unchanged body weight. They also exhibited increased plasma calcium and reduced 25-OH vitamin D levels without changes in phosphate or magnesium concentrations. Plasma ATP and pyrophosphate levels were significantly reduced, indicating impaired systemic anti-calcifying capacity. High fructose intake induced marked hepatic mitochondrial dysfunction, characterized by reduced ATP synthesis, increased H₂O₂ production, decreased mitochondrial membrane potential, impaired respiratory chain activity, and reduced oxygen consumption. In the aorta, fructose feeding increased calcification, decreased extracellular pyrophosphate synthesis, and enhanced pyrophosphate degradation. Dual inhibition of TNAP and eNTPD1 significantly reduced aortic calcification ex vivo, supporting the role of pyrophosphate-regulating enzymes in fructose-induced vascular mineralization.\n\nConclusion: These findings show that chronic fructose intake disrupts both systemic and local pyrophosphate homeostasis promoting a pro-calcifying environment. Targeting pyrophosphate-regulating pathways may represent a therapeutic strategy to prevent fructose-associated aortic calcification.\n\nGraphical Abstract: Chronic fructose intake impairs hepatic mitochondrial function and reduces systemic ATP and pyrophosphate availability. In parallel, increased TNAP- and eNTPD1-dependent extracellular nucleotide metabolism in the aortic wall reduces local pyrophosphate availability, thereby increasing susceptibility to aortic calcification.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s10020-026-01597-z.",
  "abstract_shown": true,
  "affiliations": [
    "Metabolic Homeostasis and Vascular Calcification Research Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Campus Vida, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain",
    "Health Research Institute of Santiago de Compostela (IDIS), Travesia da Choupana S/N, Santiago de Compostela, 15706 Spain",
    "Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Alicia Flores-Roco"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Ricardo Villa-Bellosta",
      "orcid": "0000-0002-1680-552X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e2jeb06n330ej.bib",
  "cited_by": 0,
  "doi": "10.1186/s10020-026-01597-z",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13732832/",
  "id": "e2jeb06n330ej",
  "issns": [
    "1076-1551",
    "1528-3658"
  ],
  "landing_url": "https://doi.org/10.1186/s10020-026-01597-z",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2712|Diet, Metabolism, and Disease"
    ]
  ],
  "openalex": "W7201911586",
  "pdf_url": null,
  "pmcid": "PMC13732832",
  "pmid": "42983278",
  "published": "2026-08-07",
  "publisher": "The Feinstein Institute for Medical Research",
  "ris": "https://research.draconitic.com/paper/e2jeb06n330ej.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:22:44Z",
      "native_id": "PMC13732832",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s10020-026-01597-z"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2712|Diet, Metabolism, and Disease",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Chronic fructose intake disrupts extracellular ATP–pyrophosphate homeostasis and increases susceptibility to aortic calcification",
  "title_text": "Chronic fructose intake disrupts extracellular ATP–pyrophosphate homeostasis and increases susceptibility to aortic calcification",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:22:44Z",
  "url": "https://research.draconitic.com/paper/e2jeb06n330ej",
  "venue": "Molecular Medicine",
  "versions": []
}