{
  "abstract": "Purpose: Anemia is a recognized complication of hypothyroidism, but disease-level genetic studies have not identified a clear erythroid cell-intrinsic target. We integrated genetic validation, molecular-QTL prioritization, and replicated triiodothyronine (T3)-responsive erythroid experiments to identify candidates linking hypothyroidism liability to anemia.\n\nMaterials and methods: Two-sample Mendelian randomization (MR) assessed genetically predicted hypothyroidism and anemia. Source metadata were reviewed for possible sample overlap, and two cross-biobank forward validations were performed. Strict reverse MR used the original OpenGWAS identifiers; because anemia provided no genome-wide-significant instruments, a post hoc analysis used p < 5 × 10 ⁻⁶ . Non-major histocompatibility complex (MHC) methylation summary-based Mendelian randomization (SMR) and whole-blood expression SMR were integrated, followed by a public fine-mapping/colocalization lookup for two acyl-CoA synthetase long-chain family member 5 ( ACSL5 ) cytosine-phosphate-guanine (CpG) sites and the ACSL5 eQTL. ACSL5 was examined in three independent hemin-induced K562, a human chronic myelogenous leukemia cell line experiments with or without T3; Triacsin C and oleic acid-bovine serum albumin (BSA) served as pathway-level perturbations.\n\nResults: Primary inverse-variance weighted (IVW) analysis associated hypothyroidism liability with higher anemia odds (OR = 1.0304; 95% CI, 1.0195–1.0414; p = 3.42 × 10 ⁻⁸ ). Both primary genome-wide association studies (GWASs) were UK Biobank-derived, and their exact participant overlap could not be determined from public summary-level information. A participant-independent FinnGen hypothyroidism-to-UK Biobank anemia validation reproduced the positive direction (28 instruments; IVW beta = 0.001448, p = 4.14 × 10 ⁻⁴ ); the complementary UK Biobank hypothyroidism-to-FinnGen anemia analysis was also positive. Strict original-ID reverse MR was not estimable; the exploratory eight-instrument analysis was null and heterogeneous. Six non-MHC CpGs passed Bonferroni correction, including two mapped to ACSL5 , while whole-blood ACSL5 expression showed an inverse SMR estimate. The public lookup returned no pairwise CpG-expression colocalization. In all three K562 experiments, hemin plus T3 increased HBA1 , HBA2 , GYPA , and ACSL5 expression. Triacsin C suppressed erythroid-marker expression, whereas oleic acid-BSA produced a partial increase without exogenous T3.\n\nConclusion: Cross-scale evidence prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia and implicates long-chain fatty-acid handling as a research direction. However, negative CpG-expression colocalization and nongene-specific pharmacological interventions preclude a mechanistic conclusion. Direct ACSL5 perturbation and primary erythroid-cell validation are required.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Hematology, The People’s Hospital of Jianyang City"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Hui Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Tao Jiang"
    },
    {
      "affs": [
        0
      ],
      "name": "Huan Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Mei Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Sixi Xie"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/49fszqq8bv54y.bib",
  "cited_by": 0,
  "doi": "10.3389/fendo.2026.1943954",
  "fulltext_url": "https://europepmc.org/articles/PMC13686861",
  "id": "49fszqq8bv54y",
  "issns": [
    "1664-2392"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1943954/full",
  "language": "eng",
  "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",
      "1311|Genetic Associations and Epidemiology"
    ]
  ],
  "openalex": "W7220927285",
  "pdf_url": "https://europepmc.org/articles/PMC13686861?pdf=render",
  "pmcid": "PMC13686861",
  "pmid": "42922834",
  "published": "2026-10-08",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/49fszqq8bv54y.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:20Z",
      "native_id": "10.3389/fendo.2026.1943954",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1943954/full"
    },
    {
      "first_seen": "2026-10-30T12:20:36Z",
      "native_id": "MED:42922834",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42922834"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genetic Associations and Epidemiology",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Cross-scale genetic, molecular, and cellular triangulation prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia",
  "title_text": "Cross-scale genetic, molecular, and cellular triangulation prioritizes ACSL5 as a T3-responsive candidate linking hypothyroidism liability to anemia",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:36Z",
  "url": "https://research.draconitic.com/paper/49fszqq8bv54y",
  "venue": "Frontiers in Endocrinology",
  "versions": []
}