尽管实施了新的治疗方案并进行了广泛的研究工作，但化疗耐药性仍然是治疗急性髓系白血病（AML）的巨大挑战。值得注意的是，溶酶体参与化疗耐药性引发了人们对开发溶酶体靶向疗法的兴趣，以使肿瘤细胞对目前批准的化疗敏感或作为创新的药理学方法。此外，由于溶酶体膜上的离子通道是溶酶体功能的关键调节因子，因此它们具有作为增强化疗敏感性的新靶点的潜力。在这里，我们发现溶酶体阳离子通道，即瞬时受体电位粘脂蛋白 1 (TRPML1)，在 AML 细胞中表达升高。单独抑制TRPML1不会影响AML细胞的增殖和凋亡。重要的是，TRPML1 的抑制证明了调节 AML 细胞对化疗药物敏感性的潜力。对潜在机制的探索表明，抑制 TRPML1 会损害自噬，同时增加 AML 细胞中活性氧 (ROS) 的产生和 ROS 介导的脂质过氧化 (Lipid-ROS)。最后，在人类白血病小鼠模型中，TRPML1 的敲低显着降低了化疗后 OCI-AML3 肿瘤的生长。总之，靶向 TRPML1 代表了一种有前途的联合治疗方法，旨在增强治疗 AML 的化学敏感性。© 2024。作者获得 Springer Science Business Media, LLC（Springer Nature 旗下公司）的独家许可。

Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid leukemia (AML). Notably, the involvement of lysosomes in chemoresistance has sparked interest in developing lysosome-targeted therapies to sensitize tumor cells to currently approved chemotherapy or as innovative pharmacological approaches. Moreover, as ion channels on the lysosomal membrane are critical regulators of lysosomal function, they present potential as novel targets for enhancing chemosensitivity. Here, we discovered that the expression of a lysosomal cation channel, namely transient receptor potential mucolipin 1 (TRPML1), was elevated in AML cells. Inhibiting TRPML1 individually does not impact the proliferation and apoptosis of AML cells. Importantly, inhibition of TRPML1 demonstrated the potential to modulate the sensitivity of AML cells to chemotherapeutic agents. Exploration of the underlying mechanisms revealed that suppression of TRPML1 impaired autophagy while concurrently increasing the production of reactive oxygen species (ROS) and ROS-mediated lipid peroxidation (Lipid-ROS) in AML cells. Finally, the knockdown of TRPML1 significantly reduced OCI-AML3 tumor growth following chemotherapy in a mouse model of human leukemia. In summary, targeting TRPML1 represents a promising approach for combination therapy aimed at enhancing chemosensitivity in treating AML.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.