Evidence map›Paper›PMID 39998898›Full record

ArticleThe Journal of clinical investigation2025

An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma.

Annegret Holm, Matthew S Graus, Jill Wylie-Sears, Jerry Wei Heng Tan, Maya Alvarez-Harmon, Luke Borgelt, Sana Nasim, Long Chung, Ashish Jain, Mingwei Sun and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed.

  1. Review
  2. Article
  3. R-(+)-propranolol for infantile hemangioma:Frontiers in medicine · 2026
    Review
  4. Review
  5. Article
  6. Review
  7. Review
  8. Article
  9. Article
  10. Article
  11. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

20 authors.

Annegret HolmVascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Matthew S GrausThe David Richmond Laboratory for Cardiovascular Development: Gene Regulation and Editing, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.
Jill Wylie-SearsVascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jerry Wei Heng TanVascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Maya Alvarez-HarmonVascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Luke BorgeltVascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Sana NasimVascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Long ChungThe David Richmond Laboratory for Cardiovascular Development: Gene Regulation and Editing, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.
Ashish JainResearch Computing, Information Technology, Boston Children's Hospital, Boston, Massachusetts, USA.
Mingwei SunResearch Computing, Information Technology, Boston Children's Hospital, Boston, Massachusetts, USA.
Liang SunResearch Computing, Information Technology, Boston Children's Hospital, Boston, Massachusetts, USA.
Pascal BrouillardHuman Molecular Genetics, de Duve Institute, University of Louvain, VASCERN-VASCA European Reference Center, Brussels, Belgium.
Ramrada LekwuttikarnDepartment of Dermatology, Lucile Packard Children's Hospital at the Stanford University School of Medicine, Palo Alto, California, USA.
Yanfei QiThe David Richmond Laboratory for Cardiovascular Development: Gene Regulation and Editing, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.
Joyce TengDepartment of Dermatology, Lucile Packard Children's Hospital at the Stanford University School of Medicine, Palo Alto, California, USA.
Miikka VikkulaHuman Molecular Genetics, de Duve Institute, University of Louvain, VASCERN-VASCA European Reference Center, Brussels, Belgium.
Harry KozakewichDepartment of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
John B MullikenDepartment of Plastic and Oral Surgery, Boston Children's Hospital; Department of Surgery, Harvard Medical School; Boston, Massachusetts, USA.
Mathias FrancoisThe David Richmond Laboratory for Cardiovascular Development: Gene Regulation and Editing, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.
Joyce BischoffVascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Funding

Blood vessel assembly from multipotent hemangioma-derived stem cellsR01HL096384 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI Joyce E. Bischoff · 2009 to 2026
$7.7M
NHLBI NIH HHS R01 HL096384
6 · The paper itself

Abstract

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis, and regression. Propranolol, the mainstay of treatment, inhibits IH vessel formation via a β-adrenergic receptor-independent off-target effect of its R(+) enantiomer on endothelial SOX18 - a member of the SOX (SRY-related HMG-box) family of transcription factors. Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss and gain of function of SOX18 confirmed it is both necessary and sufficient for R(+) propranolol suppression of the MVP, including regulation of sterol regulatory element-binding protein 2 (SREBP2) and the rate-limiting enzyme HMG-CoA reductase (HMGCR). A biological relevance of the endothelial SOX18-MVP axis in IH patient tissue was demonstrated by nuclear colocalization of SOX18 and SREBP2. Functional validation in a preclinical IH xenograft model revealed that statins - competitive inhibitors of HMGCR - efficiently suppress IH vessel formation. We propose an endothelial SOX18-MVP axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. The pleiotropic effects of R(+) propranolol and statins along the SOX18-MVP axis to disable an endothelial cell-specific program may have therapeutic implications for other vascular disease entities involving pathological vasculogenesis and angiogenesis.

Indexed as

Drug RepositioningHemangiomaHydroxymethylglutaryl-CoA Reductase InhibitorsMevalonic AcidNeoplasm ProteinsPropranololSOXF Transcription FactorsAnimalsHumansHydroxymethylglutaryl CoA ReductasesInfantMiceSignal TransductionSterol Regulatory Element Binding Protein 2Xenograft Model Antitumor AssaysHMGCR protein, humanHydroxymethylglutaryl-CoA Reductase InhibitorsHydroxymethylglutaryl CoA ReductasesMevalonic AcidNeoplasm ProteinsPropranololSOX18 protein, humanSOXF Transcription FactorsSREBF2 protein, humanSterol Regulatory Element Binding Protein 2AngiogenesisCholesterolEndothelial cellsTranscriptionVascular biology

Identifiers

PMID39998898
PMCPMC11957709

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.