Abstract: Objective:To explore the mechanism of 2-dodecyl-6-methoxy-2, 5-diene-1, 4-cyclohexanedione(DMDD) isolated from the root of Averrhoa carambola L.on the inhibition of endoplasmic reticulum stress(ERS) in mice with type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD)by regulating the JNK/P38MAPK pathway.Methods:The C57BL/6J mice were divided into normal group, mod-el group, 4-phenyl butyric acid (4-PBA) group, tunicamycin (TM) group, and high-, medium-, and low-dose DMDD groups (DMDD_H, DMDD_M, DMDD_L).Streptozotocin (STZ) was injected intritoneally after 4 weeks of a continuous high-fat diet to establish a T2DM combined with the NAFLD mouse model.The fasting blood glu-cose (FBG) levels, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and blood lipid levels in liver tissue of mice were detected after continuous administration for 8 weeks.The pathological state of the liver was observed by Hematoxylin-eosin (HE) staining and Oil Red O staining, and the expressions of grp78, Chop, JNK, phosphorylated (P)-JNK, P38MAPK, P-P38MAPK, Bcl-2 and Bax proteins in liver tissues were detected by western blotting.Results: Compared with the model group, the levels of FBG, ALT, AST, TC, TG and LDL-C in DMDD groups were reduced, the level of HDL-C increased(P< 0.05), the pathological injury of liver tissue was alleviated, the protein expression levels of grp78, Chop, PJNK, Bax and P-P38MAPK decreased and the expression level of Bcl-2 protein increased(all P< 0.05).Conclusion: DMDD may ameliorate endoplasmic reticulum stress, hepatocyte injury and apoptosis in mice with T2DM combined with NAFLD by inhibiting JNK/P38MAPK pathway.