Abstract: Objective: To study the pathogenesis of hyperuricemia combined with nonalcoholic fatty liver disease (HUA-NAFLD) based on PI3K/Akt/NF-kB signaling pathway. Methods: 64 SD rats were randomly divided into blank group, HUA group, NAFLD group, and HUA-NAFLD group, 16 rats in each group. The samples were collected at the end of the 8th and 12th week, respectively. The serum biochemical indexes of the rats were detected; The pathological changes and lipid deposition in liver tissue were observed by hematoxylin-eosin staining (HE) and Oil Red O staining; the expression levels of PI3K/Akt/NF-kB signaling pathway-related proteins in liver tissue were detected by Western blot. Results: Compared with the other three groups, the liver index of the rats in the HUA-NAFLD group was significantly increased (P<0.05). Compared with the blank group, the levels of UA and LDL in the HUA group were increased, the levels of HDL in the NAFLD group were decreased, the levels of UA, CHOL, TG and LDL in the HUA-NAFLD group were increased, and the levels of HDL were decreased (P＜0.05); Compared with the HUA-NAFLD group, the levels of CHOL, TG and LDL were decreased in the HUA group, and the levels of UA, TG and LDL in the NAFLD group were decreased (P＜0.05). The results of HE and oil red O staining showed that compared with the other three groups, rat liver cells in the HUA-NAFLD group had a large number of fat vacuoles, blurred liver cord structure and more severe lesions. The WB results showed that compared with the blank group, the phosphorylation levels of AKT and p65 in the NAFLD group were significantly increased, and the phosphorylation levels of AKT, PI3K, p65 and IKKβ in the HUA-NAFLD group were significantly increased, and compared with the HUA-NAFLD group, the phosphorylation levels of AKT and p65 in the HUA-NAFLD group decreased significantly(P<0.05). The phosphorylation level of IKKβ decreased significantly in the HUA group, and compared with the HUA group, the phosphorylation level of p65 in the NAFLD group increased significantly (P<0.05). Conclusion: Compared with the single disease group, the HUA-NAFLD group has more abnormal biochemical indexes and more severe liver lesions. The PI3K/Akt/NF-KB signaling pathway may play an important role in the pathogenesis of HUA, NAFLD and HUA-NAFLD.