Discovery of a mitochondria-targeted propranolol conjugate PL37 that induces mitophagy for potent anti-hemangioma activity

Propranolol is the first-line therapy for infantile hemangioma (IH), yet its clinical utility is limited by systemic adverse effects, variable patient response, and an incompletely defined mechanism of action. To develop a more effective and mechanism-driven therapeutic strategy, we designed and synthesized a series of propranolol-peptide conjugates incorporating distinct targeting motifs. Among them, the mitochondria-targeted derivative PL37 exhibited markedly enhanced anti-hemangioma activity. PL37 potently inhibited endothelial cell proliferation, migration, invasion, and tube formation, and significantly induced Apoptosis in both human umbilical vein endothelial cells and hemangioma-derived endothelial cells. Mechanistic studies demonstrated that PL37 triggers severe mitochondrial dysfunction, including excessive Reactive Oxygen Species generation, mitochondrial membrane potential collapse, and structural disruption. Notably, PL37 activates Mitophagy, leading to mitochondrial quality-control dysregulation and Apoptosis via a mitochondria-dependent pathway, a mechanism distinct from β-adrenergic receptor blockade. In vivo, PL37 significantly suppressed tumor growth and angiogenesis in a hemangioma xenograft model without observable toxicity. These findings establish mitochondrial targeting as a viable strategy to enhance propranolol efficacy and identify PL37 as a promising lead for the development of next-generation anti-hemangioma agents.