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Brefeldin A通过内质网应激和自噬抑制骨髓增生异常肿瘤(英文)

贺小丽^1,2, 王彦鹏^1,3, 杨超颖^1,3, 孙曙明^1,3,*

¹中南大学生命科学学院，长沙 410011；²昆山市中医医院中心实验室，昆山 215300；³中南大学血液学基础与应用湖南省重点实验室，长沙 410011

摘要

骨髓增生异常肿瘤(myelodysplastic neoplasms, MDS)是一种克隆恶性骨髓疾病，具有高度异质性，且向急性髓系白血病(acute myeloid leukemia, AML)转化风险较高。但MDS患者病程进展差异显著，临床可用治疗药物匮乏。布雷菲德菌素A (Brefeldin A, BFA)是一种天然抗生素，其抗MDS作用和分子机制尚未被阐明。本研究选取SKM-1、MDS-L细胞系及MDS患者原代骨髓样本，综合采用CCK-8 实验、流式细胞术、透射电子显微镜、RT-qPCR、免疫荧光染色、转录组测序和蛋白质免疫印迹，系统研究BFA对MDS细胞增殖、细胞周期、内质网应激(endoplasmic reticulum stress, ERS)和自噬的影响，并使用小鼠异种移植模型完成体内抗肿瘤实验。结果显示，BFA可显著抑制MDS细胞和骨髓单核细胞(bone marrow mononuclearcells, BMMCs)的增殖。机制上，BFA通过激活肌醇需求酶1α (inositol-requiring enzyme 1alpha, IRE1α)通路诱导ERS，ERS继而启动自噬，引发细胞周期在G2/M期阻滞，最终发挥抗MDS作用。体内实验初步证实BFA可有效延缓MDS进展。本研究揭示了BFA抑制MDS的主要分子机制，为将其开发为新型MDS治疗药物提供了理论基础。

关键词： 骨髓增生异常肿瘤; Brefeldin A; 自噬; 内质网应激

Myelodysplastic neoplasms are inhibited by Brefeldin A through endoplasmic reticulum stress and autophagy

HE Xiao-Li^1,2, WANG Yan-Peng^1,3, YANG Chao-Ying^1,3, SUN Shu-Ming^1,3,*

¹School of Life Sciences, Central South University, Changsha 410011, China；²Department of Central Laboratory, Kunshan Hospital of Chinese Medicine, Kunshan 215300, China；³Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410011, China

Abstract

Myelodysplastic neoplasms (MDS) are a clonal malignant bone marrow disease with high heterogeneity and a high risk of transformation into acute myeloid leukemia (AML). However, the progression of MDS varies significantly, and the available therapeutic drugs are limited. Brefeldin A (BFA), a natural antibiotic, has not been systematically elucidated for its anti-MDS activity and underlying molecular mechanisms. In this study, SKM-1 and MDS-L cell lines and patient primary bone marrow samples were adopted. Multiple experimental approaches, including CCK-8 assay, colony formation assay, flow cytometry, transmission electron microscopy, RT-qPCR, immunofluorescence staining, transcriptome sequencing, and Western blot, were comprehensively utilized to systematically investigate the effects of BFA on MDS cell proliferation, cell cycle, endoplasmic reticulum stress (ERS), and autophagy. The in vivo anti-tumor validation was conducted using mouse xenograft models. The results showed that BFA significantly inhibited the proliferation of MDS cell lines and patient-derived bone marrow mononuclear cells (BMMCs). Mechanistically, BFA activated the inositol-requiring enzyme 1alpha (IRE1α) pathway to trigger ERS, and then ERS initiated autophagy and caused cell cycle arrest at G2/M phase, ultimately exerting its anti-MDS effect. In vivo experiments preliminarily confirmed that BFA could effectively inhibit MDS progression. These results suggest the fundamental mechanisms by which BFA suppresses MDS, providing a theoretical basis for its development as a new therapeutic drug for MDS.

Key words: myelodysplastic neoplasms; Brefeldin A; autophagy; endoplasmic reticulum stress

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通讯作者：孙曙明　　E-mail:

DOI: 10.13294/j.aps.2026.0078

引用本文：

贺小丽, 王彦鹏, 杨超颖, 孙曙明. Brefeldin A通过内质网应激和自噬抑制骨髓增生异常肿瘤(英文)[J]. 生理学报 2026; 78 (4): 904-920.

HE Xiao-Li, WANG Yan-Peng, YANG Chao-Ying, SUN Shu-Ming. Myelodysplastic neoplasms are inhibited by Brefeldin A through endoplasmic reticulum stress and autophagy. Acta Physiol Sin 2026; 78 (4): 904-920