鞘脂代谢在血液系统恶性肿瘤中的研究与进展

Research and Advances in Sphingolipid Metabolism in Hematological Malignancies

摘要: 鞘脂代谢失衡在血液系统恶性肿瘤中具有多层面的影响。早期研究在HL-60白血病细胞中首先将鞘脂与细胞凋亡联系起来，此后大量工作不断拓展该领域。现有证据表明，以神经酰胺为代表的鞘脂分子可能适合作为联合治疗策略的一部分，用于增强抗白血病效应并降低对常规治疗的耐受/抗性。此外，针对鞘脂通路关键环节的药物抑制(如鞘氨醇激酶抑制剂)在多种白血病模型中可显著削弱肿瘤细胞生存；酸性神经酰胺酶抑制剂在急性髓系白血病中也显示出潜力。以鞘脂代谢重编程为核心的靶向策略，有望与现有靶向及免疫治疗形成协同疗效。未来研究需突破整合多组学与单细胞/空间技术的通用研究范式，结合鞘脂领域的独特性提出亟待解决的关键科学问题，重点探究鞘脂代谢如何与表观遗传重编程、免疫逃逸等其他癌症核心标志进行精确的机制串联，同时攻克鞘脂靶向药物研发中，因鞘脂在正常组织中的生理功能所带来的潜在脱靶毒性难题，为鞘脂生物标志物的临床转化和靶向干预方案的制定提供更具针对性的理论支撑。

Abstract: Imbalances in sphingolipid metabolism have multifaceted effects in hematologic malignancies. Early studies first linked sphingolipids to apoptosis in HL-60 leukemia cells, and since then, extensive research has continued to expand this field. Current evidence suggests that sphingolipid molecules, particularly ceramides, may be suitable as part of combination therapy strategies to enhance antileukemic effects and reduce tolerance or resistance to conventional treatments. Furthermore, pharmacological inhibition of key steps in the sphingolipid pathway (such as sphingosine kinase inhibitors) significantly impairs tumor cell survival in various leukemia models; and acid sphingolipase inhibitors have also demonstrated potential in acute myeloid leukemia. Targeted strategies centered on the reprogramming of sphingolipid metabolism are expected to produce synergistic effects with existing targeted and immunotherapies. Future research must transcend the conventional research paradigm of integrating multi-omics with single-cell and spatial technologies, identifying critical scientific questions that urgently need to be addressed in light of the unique characteristics of the sphingolipid field, with a focus on elucidating the precise mechanistic links between sphingolipid metabolism and other core cancer hallmarks, such as epigenetic reprogramming and immune evasion. Concurrently, efforts must address the challenge of potential off-target toxicity in sphingolipid-targeted drug development—arising from the physiological functions of sphingolipids in normal tissues—to provide more targeted theoretical support for the clinical translation of sphingolipid biomarkers and the formulation of targeted intervention strategies.