{
  "abstract": "Objective: Anemia affects over two billion people globally, and ESA resistance poses major clinical hurdles. HIF-2α governs erythropoiesis, yet how AMPK/mTOR energy sensors regulate HIF-2α in erythroid cells remains unclear. This study explored whether AMPK activation stabilizes HIF-2α via impaired VHL binding to boost erythroid differentiation under anemic stress through mTOR signaling.\n\nMethods: UT-7/EPO cells were cultured under 1% O2 with low EPO to mimic anemic stress, treated with AMPK/mTOR pharmacological modulators. CHX chase and Co-IP detected HIF-2α stability and VHL interaction; Ser672 phosphorylation, erythroid and iron-related genes, hepcidin and intracellular iron were measured.\n\nResults: Anemic stress suppressed cell viability, stabilized HIF-2α, activated AMPK and inhibited mTOR, upregulated erythroid markers and triggered apoptosis. AICAR extended HIF-2α half-life, disrupted HIF-2α-VHL binding and elevated Ser672 phosphorylation, while mTOR activator MHY1485 reversed these effects. AMPK activation elevated EPOR, DMT1, FPN1, lowered hepcidin and ferritin, and restored intracellular iron; these effects vanished upon HIF-2α knockdown or mTOR overactivation.\n\nConclusions: AMPK stabilizes HIF-2α by blocking VHL binding to facilitate erythroid maturation and iron homeostasis under anemic stress via mTOR. The AMPK/mTOR/HIF-2α cascade controls stress erythropoiesis, and targeting this axis may treat ESA-insensitive anemia.",
  "abstract_shown": true,
  "affiliations": [
    "The College of Food and Health of Guangzhou City Polytechnic , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yun Cen"
    },
    {
      "affs": [
        0
      ],
      "name": "Pingjing Cai"
    },
    {
      "affs": [
        0
      ],
      "name": "Jinjin Jiang"
    },
    {
      "affs": [
        0
      ],
      "name": "Lihua Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yiwei Hua"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6fb3ad0ayzr00.bib",
  "cited_by": 0,
  "doi": "10.3389/fphys.2026.1932780",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719455/?tool=EBI",
  "id": "6fb3ad0ayzr00",
  "issns": [
    "1664-042X"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13719455",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2720|Erythropoietin and Anemia Treatment"
    ]
  ],
  "openalex": "W7222447919",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719455/pdf/?tool=EBI",
  "pmcid": "PMC13719455",
  "pmid": "42964228",
  "published": "2026-10-16",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/6fb3ad0ayzr00.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:36Z",
      "native_id": "PMC:PMC13719455",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13719455"
    },
    {
      "first_seen": "2026-11-02T12:23:25Z",
      "native_id": "PMC13719455",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fphys.2026.1932780"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2720|Erythropoietin and Anemia Treatment",
      "subfield": "general"
    }
  ],
  "title": "AMPK activation stabilizes HIF-2α by disrupting VHL binding and promotes erythroid differentiation under anemic stress via the mTOR pathway",
  "title_text": "AMPK activation stabilizes HIF-2α by disrupting VHL binding and promotes erythroid differentiation under anemic stress via the mTOR pathway",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:31Z",
  "url": "https://research.draconitic.com/paper/6fb3ad0ayzr00",
  "venue": "Frontiers in physiology",
  "versions": []
}