{
  "abstract": "Background: Exposure to high levels of ionizing radiation or radiotherapy involving high-dose radiation can cause severe damage to healthy intestinal tissue. Intestinal stem cells (ISCs) play a crucial role in maintaining intestinal homeostasis and promoting epithelial regeneration. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate stem cell function. Peroxisome proliferator-activated receptor delta (PPARδ), a subtype of PPARs, can be activated by the synthetic agonist GW501516. Nevertheless, the precise mechanisms by which PPARδ modulates intestinal stem cell activity remain to be fully elucidated.\n\nMethods: A mouse model of ionizing radiation (IR)-induced intestinal injury was established by total body irradiation (TBI) with a 60Co source at a dose of 9.5 Gy in 6- to 8-week-old male C57BL/6 mice. Transcriptomic changes were screened by RNA sequencing (RNA-seq) and validated by quantitative real-time PCR (qRT-PCR). The PPARδ agonist GW501516, the PPARδ inhibitor fisetin, and β-hydroxybutyrate (β-OHB) were administered to evaluate their effects on IR-induced intestinal injury. Histopathological and tissue changes were assessed by hematoxylin and eosin (H&E) staining, Ki67 and OLFM4 immunofluorescence (IF), Lgr5 fluorescence in situ hybridization (FISH), and intestinal organoid assays. The expression of related genes and proteins was further validated by qRT-PCR and Western blotting. Statistical analyses were performed using SPSS software (IBM, Armonk, NY, USA). A P value < 0.05 was considered statistically significant.\n\nResults: GW501516 attenuated IR-induced intestinal injury, increased intestinal crypt survival, and enhanced the number of ISCs after lethal IR in vivo. Organoid experiments further demonstrated that GW501516 promoted ISC proliferation and differentiation following IR exposure. Conversely, fisetin, a PPARδ inhibitor, did not provide radioprotection either in vivo or in vitro. Our findings revealed that activation of PPARδ increased Hmgcs2 expression, which encodes the rate-limiting enzyme involved in ketone body production, including β-OHB. Furthermore, animal and organoid experiments demonstrated that β-OHB exerted radioprotective effects, as evidenced by improved intestinal crypt survival and increased ISC numbers after lethal IR exposure in vivo.\n\nConclusion: We demonstrated that the PPARδ-Hmgcs2 ketone body signaling pathway mediates ISC regeneration after IR exposure and that modulation of PPARδ activity alters ISC function. Therefore, targeting the PPARδ-Hmgcs2 ketogenic axis may represent a potential therapeutic strategy for alleviating radiation-induced enteritis.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Radiation Medicine, Faculty of Naval Medicine, Naval Medical University, Shanghai, China",
    "Department of Gastroenterology, Naval Medical Center, Naval Medical University of Chinese PLA",
    "School of Public Health, Wenzhou Medical University, Wenzhou, China",
    "Naval Medical Center, Naval Medical University, Shanghai, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yuhan Gan",
      "orcid": "0000-0003-3169-4757"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yu Gao"
    },
    {
      "affs": [
        2
      ],
      "name": "Liao Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Xuanlu Zhai"
    },
    {
      "affs": [
        0
      ],
      "name": "Duo Fang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuedong Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Ying Cheng"
    },
    {
      "affs": [
        1
      ],
      "name": "Jianming Cai"
    },
    {
      "affs": [
        3
      ],
      "name": "Tao Huang"
    },
    {
      "affs": [
        0
      ],
      "name": "Cong Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3psat275m9vff.bib",
  "cited_by": 0,
  "doi": "10.1177/15593258261459243",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13724967/",
  "id": "3psat275m9vff",
  "issns": [
    "1559-3258"
  ],
  "landing_url": "https://doi.org/10.1177/15593258261459243",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research Article"
    ],
    [
      "openalex",
      "1312|Peroxisome Proliferator-Activated Receptors"
    ]
  ],
  "openalex": "W7213648416",
  "pdf_url": "https://europepmc.org/articles/PMC13724967?pdf=render",
  "pmcid": "PMC13724967",
  "pmid": "42973967",
  "published": "2026-07-01",
  "publisher": "SAGE Publications",
  "ris": "https://research.draconitic.com/paper/3psat275m9vff.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:23:27Z",
      "native_id": "PMC13724967",
      "source": "pmc",
      "url": "https://doi.org/10.1177/15593258261459243"
    },
    {
      "first_seen": "2026-11-04T15:20:49Z",
      "native_id": "MED:42973967",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42973967"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Peroxisome Proliferator-Activated Receptors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "PPARδ-Hmgcs2 Ketone Body Signaling Mediates Intestinal Stem Cells Regeneration After IR Exposure",
  "title_text": "PPARδ-Hmgcs2 Ketone Body Signaling Mediates Intestinal Stem Cells Regeneration After IR Exposure",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:21:39Z",
  "url": "https://research.draconitic.com/paper/3psat275m9vff",
  "venue": "Dose-Response",
  "versions": []
}