{
  "abstract": "Myocardial infarction (MI) induces cardiac muscle death and its subsequent replacement by a noncontractile fibrotic scar, which underlies progression to heart failure. Current treatments restore blood flow and assist with cardiac workload but do not promote regeneration. We have previously shown endogenous growth of the cardiac lymphatic system following MI and further stimulation with the lymphatic endothelial specific mutated Vascular Endothelial Growth Factor-C (VEGF-C) isoform, VEGFC-C156S, resolves the immune response and improves cardiac function. However, the short half-life of VEGFC-C156S makes it suboptimal for clinical use, highlighting the need for alternative prolymphangiogenic strategies. We established a spheroid-based sprouting assay using human lymphatic endothelial cells to mimic lymphangiogenesis and performed a phenotypic screen of focused libraries of epigenetic regulators, kinase inhibitors, and stem cell modulators. Automated imaging and quantitative analysis identified several kinase inhibitors, previously characterized as GSK3ß inhibitors, as prolymphangiogenic regulators. Among them, the most potent was kenpaullone, which activated the same canonical prolymphangiogenic ERK pathway as VEGF-C, but induced a distinct transcriptional response in treated spheroids. Using kenpaullone-derived chemical probes and target-validation approaches, we identified MAP4K4 as a molecular target mediating the prolymphangiogenic effect observed. Finally, in a mouse MI model, kenpaullone enhanced cardiac lymphangiogenesis and improved cardiac function.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford OX3 7TY, United Kingdom",
    "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom",
    "Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom",
    "Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, United Kingdom"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Christophe Ravaud",
      "orcid": "0000-0002-0936-851X"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Caroline A. Cuoco",
      "orcid": "0009-0002-0690-6391"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sarah Sigal",
      "orcid": "0009-0009-9235-6058"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Hannah M. Unsworth",
      "orcid": "0009-0009-7100-2250"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Susanna T. E. Cooper",
      "orcid": "0000-0002-2960-6140"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Adam B. Lokman",
      "orcid": "0000-0002-8717-4550"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Carole J. R. Bataille"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Angela J. Russell"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Paul R. Riley",
      "orcid": "0000-0002-9862-7332"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/61aeygb4dj947.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2619427123",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13663767/",
  "id": "61aeygb4dj947",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://doi.org/10.1073/pnas.2619427123",
  "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": [
    [
      "heading",
      "403"
    ],
    [
      "heading",
      "Applied Biological Sciences"
    ],
    [
      "heading",
      "Biological Sciences"
    ],
    [
      "openalex",
      "2730|Lymphatic System and Diseases"
    ]
  ],
  "openalex": "W7220733756",
  "pdf_url": null,
  "pmcid": "PMC13663767",
  "pmid": "42837465",
  "published": "2026-10-06",
  "publisher": "National Academy of Sciences",
  "ris": "https://research.draconitic.com/paper/61aeygb4dj947.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:23:38Z",
      "native_id": "PMC13663767",
      "source": "pmc",
      "url": "https://doi.org/10.1073/pnas.2619427123"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Lymphatic System and Diseases",
      "subfield": "oncology"
    }
  ],
  "title": "Phenotypic screening identifies kenpaullone as a prolymphangiogenic compound to improve heart repair following myocardial infarction",
  "title_text": "Phenotypic screening identifies kenpaullone as a prolymphangiogenic compound to improve heart repair following myocardial infarction",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:20:52Z",
  "url": "https://research.draconitic.com/paper/61aeygb4dj947",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}