{"doi":"10.1172/jci179782","title":"An endothelial SOX18–mevalonate pathway axis enables repurposing of statins for infantile hemangioma","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.","journal":"Journal of Clinical Investigation","year":2025,"id":515437,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":651560,"name":"Matthew S. Graus","orcid":"0000-0001-5470-4837","position":1,"is_corresponding":false},{"id":459583,"name":"Jill Wylie‐Sears","orcid":"0000-0003-3305-8578","position":2,"is_corresponding":false},{"id":1316523,"name":"J. Tan","orcid":"0009-0000-1901-7070","position":3,"is_corresponding":false},{"id":1380418,"name":"Maya Alvarez-Harmon","orcid":null,"position":4,"is_corresponding":false},{"id":1321158,"name":"Luke Borgelt","orcid":null,"position":5,"is_corresponding":false},{"id":939297,"name":"Sana Nasim","orcid":"0000-0002-1110-4513","position":6,"is_corresponding":false},{"id":890322,"name":"Long Hoa Chung","orcid":"0000-0003-1834-5747","position":7,"is_corresponding":false},{"id":1340483,"name":"Ashish Jain","orcid":"0000-0001-7799-7484","position":8,"is_corresponding":false},{"id":1340484,"name":"Mingwei Sun","orcid":"0000-0002-1459-0043","position":9,"is_corresponding":false},{"id":669363,"name":"Liang Sun","orcid":"0000-0002-0321-9222","position":10,"is_corresponding":false},{"id":646064,"name":"Pascal Brouillard","orcid":"0000-0001-9548-8229","position":11,"is_corresponding":false},{"id":1340485,"name":"Ramrada Lekwuttikarn","orcid":"0000-0003-2951-2571","position":12,"is_corresponding":false},{"id":604490,"name":"Yanfei Qi","orcid":"0000-0003-1391-4111","position":13,"is_corresponding":false},{"id":638282,"name":"Joyce Teng","orcid":"0000-0002-1633-6807","position":14,"is_corresponding":false},{"id":584364,"name":"Miikka Vikkula","orcid":"0000-0002-6236-338X","position":15,"is_corresponding":false},{"id":1113999,"name":"Harry P. Kozakewich","orcid":null,"position":16,"is_corresponding":false},{"id":439156,"name":"John B. Mulliken","orcid":null,"position":17,"is_corresponding":false},{"id":499669,"name":"Mathias François","orcid":"0000-0002-9846-6882","position":18,"is_corresponding":false},{"id":381507,"name":"Joyce Bischoff","orcid":"0000-0002-6367-1974","position":19,"is_corresponding":false},{"id":1206097,"name":"Annegret Holm","orcid":"0000-0002-8691-4131","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T02:48:39.436300Z","pmid":"39998898","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}