4μ8C (7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran8-carboxaldehyde) is a small molecule inhibitor of inositol-requiring enzyme 1α (IRE1α) RNAse[1]. 4μ8C can form a Schiff base with a specific lysine located in the active site of the IRE1 RNAse domain, blocking its function[2]. 4μ8C can be used to study endoplasmic reticulum stress-related diseases (such as diabetes, neurodegenerative diseases, cancer) and inflammation regulation[3]. 4μ8C can inhibit insulin secretion independently of IRE1α RNase activity[4].
In vitro, 4μ8C (60μM) treatment of H4IIE hepatoma cells for 2-6h significantly reduced the expression of X-box binding protein 1 (XBP1s) in both control cells and cells treated with the endoplasmic reticulum stress inducer thapsigargin (Thap)[5].
In vivo, 4μ8C (10mg/kg) was intraperitoneally injected into atherosclerotic mice for 4 weeks, which significantly reduced the area of atherosclerotic lesions, significantly reduced the expression of spliced Xbp1 mRNA, and reduced the area of foam cells in mice[6]. Oral administration of 4μ8C (10, 50, 100mg/kg) to treat passive cutaneous anaphylaxis (PCA) mice inhibited the allergic response of PCA mice in a dose-dependent manner[7].
References:
[1] Chan S M H, Lowe M P, Bernard A, et al. The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant[J]. Biochemical Journal, 2018, 475(5): 923-929.
[2] Cross B C S, Bond P J, Sadowski P G, et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule[J]. Proceedings of the National Academy of Sciences, 2012, 109(15): E869-E878.
[3] Zhang Y, Zhang Y, Lu M, et al. IRE1α regulates macrophage polarization in type 2 diabetic periodontitis through promoting endoplasmic reticulum stress[J]. International Immunopharmacology, 2024, 133: 112056.
[4] Sato H, Shiba Y, Tsuchiya Y, et al. 4μ8C inhibits insulin secretion independent of IRE1α RNase activity[J]. Cell Structure and Function, 2017, 42(1): 61-70.
[5] Stewart C, Estrada A, Kim P, et al. Regulation of IRE1α by the small molecule inhibitor 4μ8c in hepatoma cells[J]. Cell Pathology, 2017, 4(1): 1-10.
[6] Tufanli O, Telkoparan Akillilar P, Acosta-Alvear D, et al. Targeting IRE1 with small molecules counteracts progression of atherosclerosis[J]. Proceedings of the National Academy of Sciences, 2017, 114(8): E1395-E1404.
[7] Nam S T, Park Y H, Kim H W, et al. Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, 4μ8C[J]. Toxicology and Applied Pharmacology, 2017, 332: 25-31.
4μ8C（7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran8-carboxaldehyde）是肌醇需求酶1α（IRE1α）RNAse的小分子抑制剂[1]。4μ8C能够与位于IRE1 RNA酶结构域活性位点的特异性赖氨酸形成席夫碱，阻断其功能[2]。4μ8C能够用于研究内质网应激相关疾病（如糖尿病、神经退行性疾病、癌症）及炎症调控[3]。4μ8C能够抑制胰岛素分泌，且不依赖于IRE1α RNase活性[4]。
在体外，4μ8C（60μM）处理H4IIE肝癌细胞细胞2-6h，在对照细胞和用内质网应激诱导剂毒胡萝卜素（Thap）处理的细胞中，均显著降低了细胞中X盒结合蛋白1（XBP1s）的表达[5]。
在体内，4μ8C（10mg/kg）通过腹腔注射治疗动脉粥样硬化小鼠4周，显著减少了小鼠动脉粥样硬化病变面积，显著减少了剪接的Xbp1 mRNA表达，减少了泡沫细胞面积[6]。4μ8C（10, 50, 100mg/kg）通过口服治疗被动皮肤过敏反应（PCA）小鼠，以剂量依赖性方式抑制了PCA小鼠的过敏反应[7]。