AbMole小讲堂丨ISRIB：整合应激反应的调控分子及其研究应用

ISRIB（Integrated Stress Response Inhibitor，AbMole，M9242）是一种小分子化合物，能够特异性抑制整合应激反应（ISR）的激活。ISR是细胞在应激条件下（如缺氧、病毒感染等）通过磷酸化真核翻译起始因子2α（eIF2α）来调控蛋白质合成的保守通路[1]。磷酸化的eIF2α会抑制鸟苷酸交换因子eIF2B的活性，从而减缓蛋白质合成[2]。ISRIB通过结合eIF2B的特定位点，逆转eIF2α磷酸化对eIF2B的抑制，恢复蛋白质翻译[3]。ISRIB（Integrated Stress Response Inhibitor，AbMole，M9242）通过调控整合应激反应表现出多种生物学效应：SRIB能减轻β淀粉样蛋白（Amyloid β Protein）诱导的神经元死亡，但不影响β淀粉样蛋白的生成[4]。在胶质母细胞瘤（GB）细胞中，ISRIB可增强细胞对Temozolomide（TMZ）和低氧诱导的凋亡的敏感性[5]。ISRIB在小鼠模型中，能改善慢性应激（CRS）诱导的抑郁样行为，表现为蔗糖偏好增加和强迫游泳试验（FST）中不动时间减少[6]。此外，ISRIB可减轻脑损伤后的认知功能衰退，并增强健康小鼠的认知能力[7]。ISRIB在结核分枝杆菌感染的小鼠模型中，通过抑制PKR介导的eIF2α磷酸化，阻断了肺肉芽肿坏死的发生[8]。这些发现表明，ISRIB可作为调控蛋白质稳态的工具分子，为理解ISR在肿瘤、免疫和神经功能中的作用提供了帮助

参考文献及鸣谢

[1] He, W.; Patil, A. S.; Xu, Y. Development and validation of a UHPLC-MS/MS method for the quantitative analysis of trans-ISRIB in human plasma. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2025, 1252, 124469.

[2] Zyryanova, A. F.; Weis, F.; Faille, A.; et al. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science (New York, N.Y.) 2018, 359(6383), 1533-1536.

[3] Zyryanova, A. F.; Kashiwagi, K.; Rato, C.; et al. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Molecular cell 2021, 81(1), 88-103.e106.

[4] Hosoi, T.; Kakimoto, M.; Tanaka, K.; et al. Unique pharmacological property of ISRIB in inhibition of Abeta-induced neuronal cell death. Journal of pharmacological sciences 2016, 131(4), 292-295.

[5] Lorenz, N. I.; Sittig, A. C. M.; Urban, H.; et al. Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide. Scientific reports 2021, 11(1), 14161.

[6] Luhong, L.; Zhou, H. M.; Tang, X. H.; et al. PERK inhibitor (ISRIB) improves depression-like behavior by inhibitions of HPA-axis over-activation in mice exposed to chronic restraint stress. Behavioural brain research 2024, 471, 115122.

[7] Anand, A. A.; Walter, P. Structural insights into ISRIB, a memory-enhancing inhibitor of the integrated stress response. The FEBS journal 2020, 287(2), 239-245.

[8] Bhattacharya, B.; Xiao, S.; Chatterjee, S.; et al. The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas. The Journal of clinical investigation 2021, 131(3).