{
  "abstract": "Background: Emerging evidence highlights the anti-tumor properties of Glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, their synergistic potential with standard chemotherapy remains largely unexplored.\n\nMethods: Data from Genome-wide association study (GWAS) were used to select single-nucleotide polymorphisms (SNPs) strongly associated with lipid-lowering drug targets as instrumental variables. Causal effects were assessed primarily using the inverse variance weighted (IVW) method, supported by comprehensive sensitivity analyses to control for pleiotropy and heterogeneity. These Mendelian randomization (MR) findings were further validated through in vitro functional assays (cell viability, apoptosis, and Western blot) and an in vivo tumor-bearing mouse model.\n\nResults: Glucagon-like peptide-1 receptor (GLP-1R) activity showed a significantly positive causal relationship with dihydrofolate reductase (DHFR; β = 0.323, P = 6.02 × 10 ⁻¹⁷ ) and apoptosis regulator Bcl-2 (β = 0.259, P = 2.1 × 10 ⁻¹¹ ) but a negative relationship with ribonucleoside-diphosphate reductase large subunit (RRM1; β = −0.12, P = 2.32 × 10 ⁻³ ). Functional experiments validated these genetic findings. GLP-1RA significantly enhanced the antitumoral efficacy of gemcitabine both in vitro and in vivo by repressing RRM1. Conversely, GLP-1RA attenuated the anti-tumor effects of methotrexate and paclitaxel by upregulating DHFR and Bcl-2, respectively. Notably, GLP-1RA combination therapy achieved these modulatory effects without exacerbating chemotherapy-associated systemic toxicity.\n\nConclusion: GLP1-RAs can influence the efficacy of chemotherapeutic drugs such as methotrexate, paclitaxel, and gemcitabine.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Thoracic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine",
    "Nanshan School, Guangzhou Medical University",
    "Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital",
    "The Third School of Clinical Medicine, Guangzhou Medical University",
    "Department of Otorhinolaryngology, The Seventh Affiliated Hospital of Sun Yat-Sen University",
    "Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital",
    "The Sixth School of Clinical Medicine, The Affiliated Qingyuan HospitaI (Qingyuan PeopIe’s HospitaI), Guangzhou Medical University",
    "Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University",
    "Department of Head and Neck Surgery, Sir Run Run Shaw Hospital, Zhejiang University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sha Huang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yongqi Feng"
    },
    {
      "affs": [
        2
      ],
      "name": "Yeling Liu"
    },
    {
      "affs": [
        3
      ],
      "name": "Xiaochun Mo"
    },
    {
      "affs": [
        0
      ],
      "name": "Haichuan Hu"
    },
    {
      "affs": [
        4
      ],
      "name": "Haolin Chen"
    },
    {
      "affs": [
        5
      ],
      "name": "Mengyi Han"
    },
    {
      "affs": [
        6
      ],
      "name": "Wanting Huang"
    },
    {
      "affs": [
        2
      ],
      "name": "Wantong Zheng"
    },
    {
      "affs": [
        7
      ],
      "name": "Xinting Hou"
    },
    {
      "affs": [
        3
      ],
      "name": "Runfeng Wen"
    },
    {
      "affs": [
        6
      ],
      "name": "Chenbing Liu"
    },
    {
      "affs": [
        8
      ],
      "name": "Jiahui Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yunzhen Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/40jfajataytyp.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1957757",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1957757/full",
  "id": "40jfajataytyp",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1957757/full",
  "language": "en",
  "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": [
    [
      "lcc",
      "RM1-950"
    ],
    [
      "openalex",
      "1312|Metabolism, Diabetes, and Cancer"
    ]
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  "openalex": "W7223340164",
  "pdf_url": "https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1957757/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/40jfajataytyp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:06Z",
      "native_id": "10.3389/fphar.2026.1957757",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1957757/full"
    },
    {
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Metabolism, Diabetes, and Cancer",
      "subfield": "molecular-biology"
    }
  ],
  "title": "The impact of GLP-1 receptor agonists on chemotherapeutic efficacy: insights from GWAS and experiments",
  "title_text": "The impact of GLP-1 receptor agonists on chemotherapeutic efficacy: insights from GWAS and experiments",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:44:06Z",
  "url": "https://research.draconitic.com/paper/40jfajataytyp",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}