Shikonin reverses pyruvate kinase isoform M2‐mediated propranolol resistance in infantile hemangioma through reactive oxygen species‐induced autophagic dysfunction

Infantile hemangioma (IH) is the most common benign tumor in infancy. Propranolol, a nonselective β‐adrenergic receptor blocker, is now the first‐line therapy for IH. Recently, low sensitivity to propranolol therapy has become one major reason for the failure of IH treatment. However, the exact underlying mechanisms are yet to be fully elucidated. Here, we reported that pyruvate kinase isoform M2 (PKM2), an essential glycolytic enzyme, played a critical role in regulating the progression of IH and the therapeutic resistance of propranolol treatment. Shikonin reversed the propranolol resistance in hemangioma‐derived endothelial cells and in hemangioma animal models. Moreover, shikonin combined with propranolol could induce excessive reactive oxygen species (ROS) accumulation and lead to autophagic dysfunction, which is essential for the enhanced therapeutic sensitivity of propranolol treatment. Taken together, our results indicated that PKM2 has a significant role in hemangiomas progression and therapeutic resistance; it could be a safe and effective therapeutic strategy for those hemangiomas with poor propranolol sensitivity combined with shikonin. Shikonin promotes the therapeutic efficacy of propranolol therapy by generating reactive oxygen species to mediate autophagy dysfunction.