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The development of new therapeutic avenues is hampered by the lack of animal models faithfully replicating the clinical manifestations of KLA. Here, we established a novel zebrafish model of KLA by conditionally expressing the human NRAS mutation in venous and lymphatic ECs. Mutant embryos recapitulate key clinical features of KLA, including dilated lymphatics and pericardial edema, which are reversed by trametinib, a MEK inhibitor used in KLA treatment. Leveraging this model in combination with an AI-based high-throughput drug screening platform, we identify cabozantinib, a tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as promising candidates for treating KLA. Notably, both drugs normalized sprouting and migration of cultured LECs from a KLA patient. Overall, our novel zebrafish model provides a powerful platform to dissect KLA pathogenesis and identify new therapeutic avenues.<\/jats:p>","DOI":"10.1084\/jem.20240513","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T02:20:45Z","timestamp":1751509245000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["A high-throughput zebrafish screen identifies novel candidate treatments for kaposiform lymphangiomatosis (KLA)"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9921-2083","authenticated-orcid":true,"given":"Ivan","family":"Bassi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0316ej306","id-type":"ROR","asserted-by":"publisher"}],"name":"Weizmann Institute of Science 1 Department of Immunology and Regenerative Biology, , 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