An endothelial SOX18–mevalonate pathway axis enables repurposing of statins for infantile hemangioma
(2025) Journal of Clinical Investigation — Vol. 135, n° 7, p. e179782 (2025)
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- Authors
Wylie-Sears, Jill 
Bischoff, Joyce
- 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.
- Affiliations
Boston Children’s Hospital, Harvard Medical School Vascular Biology Program, Department of Surgery Centenary Institute, University of Sydney The David Richmond Laboratory for Cardiovascular Development: Gene Regulation and Editing Boston Children’s Hospital Research Computing, Information Technology Lucile Packard Children’s Hospital at the Stanford University School of Medicine Department of Dermatology WEL Research Institute WELBIO Department Boston Children’s Hospital, Harvard Medical School Department of Pathology Boston Children’s Hospital Department of Plastic and Oral Surgery Harvard Medical School Department of Surgery University of Sydney School of Biomedical Sciences
Citations
Holm, A., Graus, M. S., Wylie-Sears, J., Tan, J. W. H., Alvarez-Harmon, M., Borgelt, L., Nasim, S., Chung, L., Jain, A., Sun, M., Sun, L., Brouillard, P., Lekwuttikarn, R., Qi, Y., Teng, J., Vikkula, M., Kozakewich, H., Mulliken, J. B., Francois, M., & Bischoff, J. (2025). An endothelial SOX18–mevalonate pathway axis enables repurposing of statins for infantile hemangioma. Journal of Clinical Investigation, 135(7), e179782. https://doi.org/10.1172/jci179782 (Original work published 2025)