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

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An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma. The Journal of clinical investigation Holm, A., Graus, M. S., Wylie-Sears, J., Tan, J. W., 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

Abstract

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis, and regression. Propranolol, the mainstay treatment, inhibits IH vessel formation via a ß-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial SRY box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells (HemSC) 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). AThe biological relevance of the endothelial SOX18-MVP axis in IH patient tissue was demonstrated by nuclear co-localization 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 novel 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-specific program may have therapeutic implications for other vascular disease entities involving pathological vasculogenesis and angiogenesis.

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