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精胺通过活性氧诱导急性髓系白血病细胞铁死亡相关表型改变

王路^1,2, 关东伟^1,2, 隆耀莹^1,2, 宁小伟^1,2,3, 余永龙^1,2, 杨世杰^1,2, 张曦^1,2,*

¹陆军军医大学第二附属医院血液病医学中心，重庆 400037；²血液病与微环境重庆市重点实验室，重庆 400037；³陆军军医大学第二附属医院日喀则分院检验科，日喀则 857000

摘要

多胺包括腐胺、亚精胺和精胺，广泛参与体内多种生理功能调控，其代谢改变与肿瘤发生、发展密切相关，干扰多胺代谢环节成为正在研究中的肿瘤治疗策略。然而，也有研究表明，精胺可抑制对去势治疗抵抗的前列腺癌的生长，提示精胺具有抗肿瘤作用。本研究旨在探讨精胺对急性髓系白血病细胞的影响。CCK8 实验、细胞计数和乳酸脱氢酶释放试验结果显示，精胺可降低MOLM-13 和HL-60 细胞的活力，抑制增殖，诱导细胞毒性。Annexin V和7-AAD结合的流式细胞术分析显示，随着精胺浓度的提高，MOLM-13 细胞中Annexin V+细胞和Annexin V+7-AAD+晚期凋亡细胞的比例增加。蛋白质组学和转录组学分析结果显示，精胺处理后MOLM-13 细胞铁死亡通路相关蛋白和基因表达发生改变。利用Liperfluo、BDP581/591 C11 及FerroOrange 探针分别检测细胞脂质过氧化、胞内游离Fe2+水平，结合透射电镜观察细胞超微结构，证实精胺可诱导MOLM-13 细胞铁死亡相关表型改变；CM-H2DCFDA和MitoSOTM Red 探针进一步检测到MOLM-13 细胞内及线粒体活性氧(reactive oxygen species, ROS)水平升高。蛋白质免疫印迹结果显示，精胺可引起MOLM-13 细胞铁死亡相关蛋白表达改变。铁死亡抑制剂liproxstatin-1 部分逆转精胺诱导的MOLM-13 细胞铁死亡相关表型改变，但不能逆转细胞活力的下降；ROS清除剂N-乙酰半胱氨酸完全逆转精胺诱导的MOLM-13 细胞铁死亡相关表型改变，并能逆转细胞活力的下降。以上结果表明，精胺可诱导急性髓系白血病细胞铁死亡相关表型改变，其机制与ROS的产生有关。

关键词： 精胺; 急性髓系白血病; 铁死亡; 活性氧

Spermine induces ferroptosis-related phenotype in acute myeloid leukemia cells through reactive oxygen species

WANG Lu^1,2, GUAN Dong-Wei^1,2, LONG Yao-Ying^1,2, NING Xiao-Wei^1,2,3, YU Yong-Long^1,2, YANG Shi-Jie^1,2, ZHANG Xi^1,2,*

¹Medical Center of Hematology, the Second Affiliated Hospital of Army Medical University, Chongqing 400037, China；²Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing 400037, China；³Department of Laboratory Medicine, Shigatse Branch, the Second Affiliated Hospital of Army Medical University, Shigatse 857000, China

Abstract

Polyamines, including putrescine, spermidine, and spermine, are widely involved in various physiological processes in vivo. Their metabolic alterations are closely associated with tumor development, and interfering with polyamine metabolism has become a therapeutic strategy under investigation for cancer. However, studies have also demonstrated that spermine can inhibit the growth of castration-resistant prostate cancer, indicating its antitumor effects. This study aimed to investigate the effects of spermine on acute myeloid leukemia (AML) cells. CCK8 assay, cell counting, and lactate dehydrogenase release assay demonstrated that spermine reduced the viability of MOLM-13 and HL-60 cells, inhibited their proliferation, and induced cytotoxicity. Flow cytometry analysis of Annexin V and 7-AAD binding in MOLM-13 cells revealed an increase in the proportion of Annexin V+ cells and Annexin V+7-AAD+ late apoptotic cells as spermine concentration increased. Proteomic and transcriptomic analyses revealed altered expression of ferroptosis pathway-related proteins and genes in MOLM-13 cells following spermine treatment. Using Liperfluo, BDP 581/591 C11, and FerroOrange probes to detect cellular lipid peroxidation and intracellular free Fe2+ levels, combined with transmission electron microscopy to observe cell ultrastructure, it was confirmed that spermine induced ferroptosis-related phenotype in MOLM-13 cells; CM-H2DCFDA and MitoSOTM Red probes further detected elevated levels of intracellular and mitochondrial reactive oxygen species (ROS), and Western blot showed that spermine caused changes in the expression of ferroptosis-related proteins. Ferroptosis inhibitor liproxstatin-1 partially reversed the spermine-induced ferroptosis-related phenotype in MOLM-13 cells, but did not reverse the decline in cell viability. In contrast, the ROS scavenger N-acetylcysteine completely reversed both the ferroptosis-related phenotype and the reduction in cell viability. These results suggest that spermine induces ferroptosis-related phenotype in AML cells, and its mechanism is associated with ROS generation.

Key words: Spermine; acute myeloid leukemia; ferroptosis; ROS

收稿日期：　　录用日期：

通讯作者：张曦　　E-mail:

DOI: 10.13294/j.aps.2026.0053

引用本文：

王路, 关东伟, 隆耀莹, 宁小伟, 余永龙, 杨世杰, 张曦. 精胺通过活性氧诱导急性髓系白血病细胞铁死亡相关表型改变[J]. 生理学报 2026; 78 (3): 693-704.

WANG Lu, GUAN Dong-Wei, LONG Yao-Ying, NING Xiao-Wei, YU Yong-Long, YANG Shi-Jie, ZHANG Xi. Spermine induces ferroptosis-related phenotype in acute myeloid leukemia cells through reactive oxygen species. Acta Physiol Sin 2026; 78 (3): 693-704 (in Chinese with English abstract).