Objective To investigate the effect of Myriocin on high fat diet induced integrated stress response and further explore the mechanism. Methods A total of 18 ApoE-/- mice were fed a high- fat diet and randomly divided into control group (n = 9, phosphate buffer solution) and Myriocin group (n = 9, phosphate buffer solution + Myriocin). The drugs were administered orally for 12 weeks. Serum lipids [total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), very low density lipoprotein- cholesterol (VLDL-C) and high density lipoprotein-cholesterol (HDL-C)] were measured. Flow-cytometric analysis was used to determine the proportion of lymphocyte antigen 6 complex (Ly - 6c)high phenotype monocytes. HE staining was performed to compare the size and detailed composition of atherosclerotic plaques and immunofluorescence staining was used to observe the expression of monocyte chemotactic protein-1 (MCP-1). Real-time fluorescence quantitative polymerase chain reaction (PCR) was used to detect the mRNA expression levels of inflammation related molecules [including pro - inflammatory factors, interleukin-1β and 6 (IL-1β and IL-6), tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF) and anti- inflammatory factor, IL-10]. In addition, the mRNA expression levels of integrated stress response related molecules [including glucose regulated protein 78 (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2 α (eIF2 α), activating transcription factor 4 and 6 (ATF4 and ATF6), endoplasmic reticulum stress - related apoptosis protein C/EBP homologous protein (CHOP) and Caspase12] were tested. The expression levels of integrated stress response related protein [including eIF2α, ATF4, inositol-requiring enzyme 1α (IRE1α) and phosphorylated IRE1α, p65 nuclear factor (p65 NF) and phosphorylated p65 NF, Caspase12 and cleaved Caspase12] were explored by Western blotting. Results 1) Treatment with Myriocin led to lower level of serum LDLC (t = 2.830, P = 0.012). 2) Myriocin suppressed monocytes differentiating toward a Ly-6chigh phenotype (t = 2.866, P = 0.011). 3) HE staining showed less atherosclerotic lesions at 200 and 300 μm distance away from the aortic valve (t = 2.281, P = 0.045; t = 3.506, P = 0.003) and less necrotic core areas (Z = - 2.870, P = 0.004) in the Myriocin group. 4) Immunofluorescence staining showed the reduction of MCP-1 protein expression in the Myriocin group; real-time fluorescence quantitative PCR showed that IL-1β mRNA (t = 3.968, P = 0.005), TNFα mRNA (t = 7.696, P = 0.000), ICAM mRNA (t = 3.294, P = 0.013), VCAM mRNA (t = 5.449, P = 0.001) and VEGF mRNA (t = 2.574, P = 0.037) were generally decreased in the Myriocin group, while IL-10 mRNA was increased (t = - 3.132, P = 0.017) in the Myriocin group. 5) Myriocin downregulated PERK mRNA (t = 4.174, P = 0.004-, eIF2α mRNA (Z = - 2.692, P = 0.007), ATF4 mRNA (t = 3.342, P = 0.012), ATF6 mRNA (t = 5.841, P = 0.001) and Caspase12 mRNA (t = 7.270, P = 0.000). 6) Western blotting showed that Myriocin suppressed the protein expression of eIF2α (t = 2.175, P = 0.047) and ATF4 (t = 2.923, P = 0.011), and the phosphorylation of p65 NF - B (t = 2.909, P = 0.011). Conclusions Myriocin could alleviate atherosclerosis progression of ApoE-/- mice by reducing integrated stress response and inflammatory response in the arterial walls. [ABSTRACT FROM AUTHOR]