急性髓系白血病（AML）是一种侵袭性血液恶性肿瘤，需要紧急治疗进展。神经酰胺是一种促进细胞死亡的信号脂质，在治疗诱导的细胞死亡中发挥着核心作用。酸性神经酰胺酶 (AC) 是一种神经酰胺消耗酶，在 AML 中过度表达，可促进白血病存活和耐药性。神经酰胺酶抑制剂 B-13 和称为二甲基甘氨酸 (DMG)-B-13 前药的下一代溶酶体定位衍生物已开发出来，但尚未在 AML 中进行测试。在这里，我们报告了 DMG-B-13 前药 LCL-805 在 AML 细胞系和主要患者样本中的体外抗白血病功效和机制。 LCL-805 抑制 AC 酶活性，增加神经酰胺总量，并降低鞘氨醇水平。在 32 种人类 AML 细胞系的细胞活力测定中，LCL-805 的 EC50 中值达到 11.7 μM。在 71 名原发性 AML 患者样本中测试单一药物时，EC50 中值达到 15.8 μM。外源性神经酰胺补充剂与 C6-神经酰胺纳米脂质体（正在进入治疗复发/难治性 AML 的 I/II 期临床试验）显着增强了 LCL-805 的杀灭作用。从机制上讲，LCL-805 拮抗 Akt 信号传导并导致铁依赖性细胞死亡，这与典型的铁死亡不同。这些发现阐明了 LCL-805 细胞毒性的关键因素，并证明了 AC 抑制与外源性神经酰胺相结合的效力。

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 μM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 μM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.