Endothelial metabolic plasticity in infantile hemangioma: evidence strength, disease phase and therapeutic readiness

Endothelial metabolism is increasingly used to explain the growth, involution and drug response of infantile hemangioma (IH), but the supporting studies differ sharply in disease relevance and validation depth. We assessed which endothelial metabolic and plasticity mechanisms are sufficiently supported to guide experiments, biomarker work or therapeutic development. We performed a structured narrative search of PubMed/MEDLINE from inception to 28 July 2026 and hand-searched the references of included studies and recent reviews. Evidence was weighted by phase-resolved human tissue, patient-derived hemangioma endothelial or stem cells, pathway-specific perturbation, orthogonal or rescue experiments, and lesion-relevant in vivo testing. PFKFB3-supported glycolysis has the most complete preclinical chain for proliferative hemangioma endothelial cells. The SOX18-mevalonate pathway is comparably well anchored during hemangioma stem-cell endothelial differentiation and supports a beta-adrenergic-receptor-independent mechanism for R(+) propranolol. AIBP/NAXE-cholesterol-HIF-1α signaling is supported by bidirectional perturbation and several animal contexts, whereas amino-acid findings remain descriptive. Endothelial-to-mesenchymal transition is not a single involution program: TGF-β1 can drive a proangiogenic state, whereas M1-associated cytokines confer mesenchymal and adipogenic competence in regression-linked models. Recent mitochondrial-targeting and cell-fate studies remain single-study, model-limited evidence. None of the proposed PFKFB3 inhibitors, statins, optically pure R(+) beta-blocker enantiomers or phase-matched combinations has established efficacy or safety for infants with IH. Current evidence prioritizes mechanisms for preclinical development, not off-label treatment. Reproducibility, infant-relevant pharmacology, developmental safety and phase-specific biomarkers are required before clinical testing.