尽管已经开发出可选择性靶向癌细胞的治疗药物，但由于药物耐受性和治疗失败导致的复发仍然是一个重要问题。高度保守的Hedgehog (HH)信号通路在发育和组织稳态方面发挥多种作用，其异常调节已知会推动多种人类恶性肿瘤的病理进程。然而，HH信号通路在介导疾病进展和药物抗性方面的作用仍不清楚，特别是对于骨髓恶性肿瘤而言。已经证实，HH通路，尤其是蛋白质Smoothened (SMO)，对于慢性骨髓性白血病（CML）干细胞命运的调控至关重要。证据表明，HH通路活性对于维持CML白血病干细胞的耐药性和存活至关重要，并且BCR-ABL1和SMO的双重抑制可能组成患者体内消灭这些细胞的有效治疗策略。本综述将探讨HH信号通路的进化起源，强调其在发育和疾病中发挥的角色，这些角色通过经典和非经典的HH信号传递介导。讨论了小分子抑制剂对HH信号通路的发展以及使用这些抑制剂作为癌症治疗药物的临床试验及其潜在抗药性机制，重点关注CML。

Despite the development of therapeutic agents that selectively target cancer cells, relapse driven by acquired drug resistance and resulting treatment failure remains a significant issue. The highly conserved Hedgehog (HH) signaling pathway performs multiple roles in both development and tissue homeostasis, and its aberrant regulation is known to drive the pathogenesis of numerous human malignancies. However, the role of HH signaling in mediating disease progression and drug resistance remains unclear. This is especially true for myeloid malignancies. The HH pathway, and in particular the protein Smoothened (SMO), has been shown to be essential for regulating stem cell fate in chronic myeloid leukemia (CML). Evidence suggests that HH pathway activity is critical for maintaining the drug-resistant properties and survival of CML leukemic stem cells (LSCs), and that dual inhibition of BCR-ABL1 and SMO may comprise an effective therapeutic strategy for the eradication of these cells in patients. This review will explore the evolutionary origins of HH signaling, highlighting its roles in development and disease, which are mediated by canonical and non-canonical HH signaling. Development of small molecule inhibitors of HH signaling and clinical trials using these inhibitors as therapeutic agents in cancer and their potential resistance mechanisms, are also discussed, with a focus on CML.