{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:31:15Z","timestamp":1784770275222,"version":"3.55.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T00:00:00Z","timestamp":1743811200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T00:00:00Z","timestamp":1743811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Res"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Infantile hemangiomas (IH) are common vascular tumors in infants, with no well-defined therapeutic agents currently available. Recent studies have explored molecular mechanisms involved in IH progression, but the lack of immortalized hemangioma-derived endothelial cell (iHemEC) models has limited drug discovery efforts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established an immortalized hemangioma-derived endothelial cell (iHemEC) expressing hemangioma markers and screened 18 potential drugs. Transcriptome profiling and Gene Set Enrichment Analysis (GSEA) were applied to assess the molecular effects of Everolimus and Sunitinib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sunitinib, Elimusertib, HIF-1 inhibitor-4, Rebastinib, and Everolimus inhibited iHemEC with lower IC\n                      <jats:sub>50<\/jats:sub>\n                      than Propranolol and Rapamycin. GSEA showed that PI3K\/AKT\/mTOR pathway was only downregulated in Everolimus treated cells. Chromosome instability was found specifically in Sunitinib treated cells, which has been reported to cause DNA damage. DNA damage induced ROS and extracellular ROS production was only observed in Sunitinib treated cells. Additionally, Sunitinib can trigger P53 activation and BCL2 downregulation with a dose of 0.2\u2009\u00b5M which is fifty times lower than the dose of Everolimus at 10\u2009\u00b5M.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We successfully developed an iHemEC model for in vitro drug screening and mechanistic study. Everolimus and Sunitinib emerged as promising therapeutic candidates for IH, providing a valuable basis for future research.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical perspectives<\/jats:title>\n                    <jats:p>\n                      Infantile hemangiomas (IH) are very common tumors in the neonatal period, with an incidence of approximately 2% to 10% among newborns, there are no well-defined therapeutic agents for IH, nor are there established human immortalized cell lines for in vitro studies. We establish an immortalized hemangioma-derived endothelial cell (iHemEC) which highly express markers of hemangioma. Drug screening was performed on iHemEC, Everolimus and Sunitinib were found efficiently induce cell death to iHemEC with much lower IC\n                      <jats:sub>50<\/jats:sub>\n                      than front line drug Propranolol. Bulk RNAseq and WB analysis showed that Everolimus specifically inhibit PI3K\/AKT\/mTOR pathway, however Sunitinib induce chromosome instability and DNA damage. Both drugs can trigger P53 dependent cell death. Our study successfully developed an iHemEC cell line suitable for in vitro drug screening and mechanistic study. Sunitinib, VEGFR inhibitor, potentially can applied for the treatment of IH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Impact<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Developed a novel immortalized hemangioma-derived endothelial cell (iHemEC) model that replicates key IH features, overcoming limitations of primary cell models.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Identified Sunitinib and Everolimus as promising therapeutic candidates with superior efficacy, supported by transcriptome and protein analyses.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Revealed distinct drug mechanisms, with Everolimus targeting PI3K\/AKT\/mTOR and Sunitinib inducing chromosome instability and DNA damage.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41390-025-04028-7","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T06:54:09Z","timestamp":1743836049000},"page":"2374-2384","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Everolimus and Sunitinib potentially work as therapeutic drugs for infantile hemangiomas"],"prefix":"10.1038","volume":"98","author":[{"given":"Rongfang","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhujue","family":"Taohuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalind","family":"Kieran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changxian","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0972-3312","authenticated-orcid":false,"given":"Jianfeng","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xusheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,5]]},"reference":[{"key":"4028_CR1","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1056\/NEJM199907153410307","volume":"341","author":"BA Drolet","year":"1999","unstructured":"Drolet, B. 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Written informed consent was obtained for the use of IH specimens in accordance with the Declaration of Helsinki principles.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have approved the publication of this manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}