R-Propranolol Promotes the Adipogenesis and Subsequent Apoptosis of Hemangioma Stem Cells through the Protein Kinase RNA-Like Endoplasmic Reticulum Kinase Signaling Pathway

Propranolol is currently the first-line therapy for infantile hemangioma (IH); however, its use is limited by notable adverse effects. The non-β-blocker enantiomer of propranolol, R-propranolol, represents a promising alternative for IH treatment. In this study, the efficacy of R-propranolol and its underlying mechanism in IH involution were investigated. The protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway was required for the adipogenic potential of hemangioma stem cells (HemSCs), whereas prolonged PERK activation led to apoptosis. R-propranolol and racemic propranolol induce comparable HemSC adipogenesis. R-propranolol showed a stronger ability to disrupt protein homeostasis in HemSCs than racemic propranolol, as indicated by increased protein misfolding and enhanced activation of the PERK signaling pathway. Notably, R-propranolol induced HemSC apoptosis more effectively than racemic propranolol. This effect was attenuated by the PERK inhibitor GSK2606414. Immunostaining of clinical specimens further showed that PERK expression was higher in involuting IH samples than in proliferating IH samples. Together, these findings demonstrate that R-propranolol promotes adipogenesis and subsequent apoptosis of HemSCs through activation of the PERK signaling pathway.