R-(+)-propranolol for infantile hemangioma: β-adrenoceptor-independent mechanisms and clinical translation prospects

Infantile hemangioma (IH) is the most prevalent benign vascular tumor in infancy, and propranolol is the first-line standard pharmacotherapy for high-risk IH. The clinically used formulation of propranolol is an equimolar 1:1 racemic mixture of two enantiomers, S-(-)-propranolol and R-(+)-propranolol. The traditional mechanistic hypothesis is centered on the β-adrenoceptor blockade pathway mediated by the S-enantiomer, yet this framework fails to fully explain the dose-response relationship and long-term involution effect of propranolol in IH treatment. Recent studies have revealed that R-(+)-propranolol, which exhibits negligible β-adrenoceptor blocking activity, exerts a remarkable and independent anti-IH effect, indicating the existence of a core β-adrenoceptor-independent mechanism of action. This review systematically integrates the preclinical evidence for the β-independent anti-IH activity of R-(+)-propranolol, elucidates the discovery logic of SOX18 as the core molecular target, identifies key translational gaps (zero clinical trials, lack of infant enantiomer-specific PK data, chiral formulation challenges), and proposes a dual-track model of propranolol action in IH. The authors further clarify the critical gaps in clinical translation in this field and provide a theoretical basis for the precision therapy of IH and the development of novel chiral pharmaceuticals.