Exendin-4是一种长效胰高血糖素样肽-1（GLP-1）类似物，通过激动G蛋白偶联受体GLP-1R发挥作用，其机制涉及增强胰岛素分泌、调节细胞增殖与分化。在细胞实验中，Exendin-4（CAS No.：141758-74-9）可诱导大鼠胰腺AR42J细胞自噬流障碍并促进凋亡，该效应与溶酶体相关膜蛋白LAMP-2的下调相关[1]。在人脐静脉内皮细胞（HUVECs）中，Exendin-4（10 nM）通过激活GLP-1R-Sirt1-Foxo1通路显著上调脂联素表达[2]，并在高糖损伤模型（100 μM葡萄糖）中通过抑制活性氧（ROS）及凋亡蛋白（如降低cleaved caspase-3、Bax，升高Bcl-2）减轻细胞损伤。Exendin-4（ CAS No.：141758-74-9）还能通过抑制mTORC1/Akt磷酸化并激活AMPK通路，抑制卵巢癌细胞系SKOV-3和OVCAR-3的增殖并促进凋亡[3]。动物实验中，Exendin-4（Exenatide，AbMole，M10034）在多种模型中展示多效性：糖尿病小鼠（T2DM模型）皮下注射Exendin-4可降低血糖，改善血脂，并下调炎症因子IL-6。 非肥胖糖尿病（NOD）小鼠经Exendin-4干预（2–8 μg/kg/天）可调节胰岛微环境，增强miR-19b表达以保护胰岛细胞[4]。Exendin-4还具有神经保护活性：新生小鼠（C57BL/6品系）缺氧缺血后，4次高剂量Exendin-4（0.5 μg/g，间隔12小时）显著减少脑损伤并维持神经保护作用[5]。 Exendin-4在肿瘤研究中也有应用，例如小鼠皮下肿瘤模型经Exendin-4（10–30 nmol/kg）处理后，肿瘤生长减慢，并伴随CD8⁺T细胞/调节性T细胞比例升高及IFN-γ、IL-2分泌增加[6]。

参考文献及鸣谢

[1] Li, Z.; Zhu, S.; Huang, L.; et al. Exendin-4 impairs the autophagic flux to induce apoptosis in pancreatic acinar AR42J cells by down-regulating LAMP-2. Biochemical and biophysical research communications 2018, 496 (2), 294-301.

[2] Wang, A.; Li, T.; An, P.; et al. Exendin-4 Upregulates Adiponectin Level in Adipocytes via Sirt1/Foxo-1 Signaling Pathway. PloS one 2017, 12 (1), e0169469.

[3] Badi, R. M.; Khaleel, E. F.; El-Bidawy, M. H.; et al. Exendin-4 Induces Cytotoxic Autophagy in Two Ovarian Cancer Cell Lines through Inhibition of Mtorc1 Mediated by Activation of AMPK and Suppression of Akt. Folia biologica 2020, 66 (5-6), 186-203.

[4] He, J.; Lian, C.; Fang, Y.; et al. The influence of exendin-4 intervention on -obese diabetic mouse blood and the pancreatic tissue immune microenvironment. Experimental and therapeutic medicine 2016, 12 (5), 2893-2898.

[5] Rocha-Ferreira, E.; Poupon, L.; Zelco, A.; et al. Neuroprotective exendin-4 enhances hypothermia therapy in a model of hypoxic-ischaemic encephalopathy. Brain : a journal of neurology 2018, 141 (10), 2925-2942.

[6] He, L.; Law, P. T. Y.; Wong, C. K.; et al. Exendin-4 Exhibits Enhanced Anti-tumor Effects in Diabetic Mice. Scientific reports 2017, 7 (1), 1791.