代谢重编程通过CASP3乳酸化促进急性淋巴细胞白血病细胞凋亡抵抗

IF 33.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-07-23 DOI:10.1186/s12943-025-02392-w

Zhi Lin, Fei Long, Jiao Liu, Rui Kang, Daniel J. Klionsky, Guido Kroemer, Daolin Tang, Minghua Yang

{"title":"代谢重编程通过CASP3乳酸化促进急性淋巴细胞白血病细胞凋亡抵抗","authors":"Zhi Lin, Fei Long, Jiao Liu, Rui Kang, Daniel J. Klionsky, Guido Kroemer, Daolin Tang, Minghua Yang","doi":"10.1186/s12943-025-02392-w","DOIUrl":null,"url":null,"abstract":"Acute lymphoblastic leukemia (ALL) is characterized by metabolic adaptations that support rapid cell proliferation and resistance to apoptosis. Our study identifies elevated sphingomyelin (SM) as a key metabolic alteration in ALL, contributing to apoptosis resistance via CASP3 (caspase 3) lactylation. Using comprehensive lipidomic analyses of plasma samples from pediatric ALL patients, we observed significantly increased SM concentrations in patients with manifest ALL compared to patients after remission. Mechanistic investigations revealed that elevated SM enhances SLC2A1-dependent glucose uptake and glycolysis, leading to increased lactate production and subsequent CASP3 lactylation on lysine residue 14, which inhibits CASP3 activation and apoptosis. Reduction of intracellular SM levels through SGMS1 knockout or SMPD3 overexpression reduced glycolytic flux and lactate levels, restored CASP3 activity and induced apoptosis in ALL cells. In vivo, SM depletion significantly suppressed ALL progression and prolonged survival in mouse models, highlighting the potential of targeting SM metabolism as a therapeutic strategy. In conclusion, our findings uncover a metabolic pathway linking lipid and glucose metabolism to apoptosis resistance in ALL.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"143 1","pages":""},"PeriodicalIF":33.9000,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Metabolic reprogramming promotes apoptosis resistance in acute lymphoblastic leukemia through CASP3 lactylation\",\"authors\":\"Zhi Lin, Fei Long, Jiao Liu, Rui Kang, Daniel J. Klionsky, Guido Kroemer, Daolin Tang, Minghua Yang\",\"doi\":\"10.1186/s12943-025-02392-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Acute lymphoblastic leukemia (ALL) is characterized by metabolic adaptations that support rapid cell proliferation and resistance to apoptosis. Our study identifies elevated sphingomyelin (SM) as a key metabolic alteration in ALL, contributing to apoptosis resistance via CASP3 (caspase 3) lactylation. Using comprehensive lipidomic analyses of plasma samples from pediatric ALL patients, we observed significantly increased SM concentrations in patients with manifest ALL compared to patients after remission. Mechanistic investigations revealed that elevated SM enhances SLC2A1-dependent glucose uptake and glycolysis, leading to increased lactate production and subsequent CASP3 lactylation on lysine residue 14, which inhibits CASP3 activation and apoptosis. Reduction of intracellular SM levels through SGMS1 knockout or SMPD3 overexpression reduced glycolytic flux and lactate levels, restored CASP3 activity and induced apoptosis in ALL cells. In vivo, SM depletion significantly suppressed ALL progression and prolonged survival in mouse models, highlighting the potential of targeting SM metabolism as a therapeutic strategy. In conclusion, our findings uncover a metabolic pathway linking lipid and glucose metabolism to apoptosis resistance in ALL.\",\"PeriodicalId\":19000,\"journal\":{\"name\":\"Molecular Cancer\",\"volume\":\"143 1\",\"pages\":\"\"},\"PeriodicalIF\":33.9000,\"publicationDate\":\"2025-07-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12943-025-02392-w\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12943-025-02392-w","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

急性淋巴细胞白血病（ALL）的特点是代谢适应，支持细胞快速增殖和抵抗凋亡。我们的研究发现鞘磷脂（SM）升高是ALL的一个关键代谢改变，通过CASP3 （caspase 3）乳酸化促进细胞凋亡抵抗。通过对儿科ALL患者血浆样本进行全面的脂质组学分析，我们观察到与缓解后的患者相比，明显ALL患者的SM浓度显著增加。机制研究表明，SM升高会增强slc2a1依赖的葡萄糖摄取和糖酵解，导致乳酸生成增加，随后在赖氨酸残基14上发生CASP3的乳酸化，从而抑制CASP3的激活和凋亡。通过敲除SGMS1或SMPD3过表达降低细胞内SM水平，可降低ALL细胞的糖酵解通量和乳酸水平，恢复CASP3活性并诱导凋亡。在小鼠模型中，SM缺失显著抑制ALL进展并延长生存期，这突出了靶向SM代谢作为治疗策略的潜力。总之，我们的发现揭示了一种将脂质和葡萄糖代谢与ALL细胞凋亡抵抗联系起来的代谢途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Metabolic reprogramming promotes apoptosis resistance in acute lymphoblastic leukemia through CASP3 lactylation

Acute lymphoblastic leukemia (ALL) is characterized by metabolic adaptations that support rapid cell proliferation and resistance to apoptosis. Our study identifies elevated sphingomyelin (SM) as a key metabolic alteration in ALL, contributing to apoptosis resistance via CASP3 (caspase 3) lactylation. Using comprehensive lipidomic analyses of plasma samples from pediatric ALL patients, we observed significantly increased SM concentrations in patients with manifest ALL compared to patients after remission. Mechanistic investigations revealed that elevated SM enhances SLC2A1-dependent glucose uptake and glycolysis, leading to increased lactate production and subsequent CASP3 lactylation on lysine residue 14, which inhibits CASP3 activation and apoptosis. Reduction of intracellular SM levels through SGMS1 knockout or SMPD3 overexpression reduced glycolytic flux and lactate levels, restored CASP3 activity and induced apoptosis in ALL cells. In vivo, SM depletion significantly suppressed ALL progression and prolonged survival in mouse models, highlighting the potential of targeting SM metabolism as a therapeutic strategy. In conclusion, our findings uncover a metabolic pathway linking lipid and glucose metabolism to apoptosis resistance in ALL.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.