{
  "abstract": "ObjectiveAortic aneurysm (AA) is a life-threatening vascular disease characterized by immune disturbance and metabolic dysregulation. Multi-omics-driven precision toxicity prediction, integrating human genetic causal inference with functional in-vitro toxicology, remains under-explored for uncovering metabolite mediators underlying AA disease risk.This study aimed to dissect metabolite-dependent causal pathways linking immune cells to AA, and evaluate dose-response cytotoxicity of key mediating metabolites toward vascular cells.MethodsTwo-sample Mendelian randomization (MR) and two-step mediation analysis were performed using European-ancestry GWAS summary datasets covering 731 immune-cell traits, 1,091 plasma metabolites, 3,230 AA cases and 475,964 controls. Complementary in-vitro CCK-8 cytotoxicity experiments on human aortic smooth muscle cells (HASMCs) were further conducted for candidate metabolites Adrenate (22:4n6) and BAFF-R.ResultsBAFF-R on CD20− (OR = 0.859, 95%CI: 0.797–0.926, P = 7.17 × 10−5) and, to a lesser extent, Granulocyte AC (OR = 0.900, 95%CI: 0.843–0.961, P = 1.57 × 10−3) emerged as candidate protective immune-cell markers for AA. Adrenate (22:4n6) and Nisinate (24:6n3) mediated 4.47% and 9.84% of these protective effects, respectively. Adrenate triggered significant dose-dependent cytotoxicity in HASMCs.ConclusionThis multi-omics genetic-toxicology study provides causal genetic evidence for immune-metabolite regulatory axes in AA pathogenesis. Notably, Adrenate presents dual biological effects: it transmits immune-protective signals but exerts direct vascular cellular toxicity. Our findings highlight the utility of MR-assisted precision toxicity prediction for disease risk evaluation and therapeutic target mining for AA.",
  "abstract_shown": true,
  "affiliations": [
    "epartment of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jia Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Bolin Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuming Hao"
    },
    {
      "affs": [
        0
      ],
      "name": "Shipan Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaonan Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Fan Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Sichong Qian"
    },
    {
      "affs": [
        0
      ],
      "name": "Haiyang Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1cj6sn7wx6ya2.bib",
  "cited_by": 0,
  "doi": "10.3389/fgene.2026.2010274",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fgene.2026.2010274/full",
  "id": "1cj6sn7wx6ya2",
  "issns": [
    "1664-8021"
  ],
  "landing_url": "https://doi.org/10.3389/fgene.2026.2010274",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH426-470"
    ],
    [
      "openalex",
      "2740|Aortic aneurysm repair treatments"
    ]
  ],
  "openalex": "W7225166961",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-03",
  "publisher": "Frontiers Media S.A.",
  "ris": "https://research.draconitic.com/paper/1cj6sn7wx6ya2.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T14:20:39Z",
      "native_id": "017ae2a41ddf4cfa90535c5d1c97534b",
      "source": "doaj",
      "url": "https://doi.org/10.3389/fgene.2026.2010274"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "journal-openalex:F13",
      "subfield": "general"
    },
    {
      "field": "biology",
      "origin": "lcc:QH426-470",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Genetic-multi-omics causal inference coupled with integrative in-vitro toxicology reveals immune-metabolite mediators for aortic aneurysm risk",
  "title_text": "Genetic-multi-omics causal inference coupled with integrative in-vitro toxicology reveals immune-metabolite mediators for aortic aneurysm risk",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T14:20:36Z",
  "url": "https://research.draconitic.com/paper/1cj6sn7wx6ya2",
  "venue": "Frontiers in Genetics",
  "versions": []
}