Objective To explore the influence of hsa_circ_0004535 on type 2 diabetes (T2DM) combined with metabolic-associated fatty liver disease (MAFLD) model mice. Methods Forty-eight healthy SPF grade Balb/c mice were selected for modeling and divided into the following groups (n=6 per group): Control group: normal feed; T2DM group: diabetes model induced by high-glucose and high-fat diet; T2DM combined MAFLD group: non-alcoholic fatty liver high-glucose and high-fat diet-induced diabetes combined with fatty liver model; T2DM combined MAFLD+hsa_circ_NC group: after 4 weeks of modeling, 10 nmol hsa_circ_NC injected into the tail vein; T2DM combined MAFLD+hsa_circ_0004535 group: after 4 weeks of modeling, 10 nmol circ_0004535 injected into the tail vein; T2DM combined MAFLD+miRNA_NC group: after 4 weeks of modeling, 10 nmol miRNA blank control injected into the tail vein; T2DM combined MAFLD+miR-1827 agomir group: after 4 weeks of modeling, 10 nmol miR-1827 agomir injected into the tail vein; and T2DM combined MAFLD+miR-1827 antagomir group: after 4 weeks of modeling, 10 nmol miR-1827 antagomir injected into the tail vein. Mouse body weight was measured after the interventions and recorded weekly. Glucose and insulin tolerance tests were performed, blood lipids and liver function were measured, the liver and insulin resistance indexes were calculated, and pathological tests (hematoxylin/ eosin (HE), oil red O, and Masson staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)) were performed to measure the degree of hepatic inflammation, fat deposition, and fibrosis. Results (1)Body weight, liver weight, liver index, insulin resistance index, and biochemical indexes were all significantly lower in the hsa_circ_0004535 injection group compared with the hsa_circ_NC injection group and the T2DM combined MAFLD group (both P<0.05). (2)Steatosis vacuoles were reduced and smaller and inflammatory cell infiltration was reduced in the T2DM combined MAFLD+circ_0004535 group, as shown by HE and oil red staining. (3)TUNEL-positive cells were significantly reduced in the T2DM combined MAFLD+hsa_circ_0004535 group (P<0.05). (4)Collagen fiber deposition was significantly reduced in the T2DM combined MAFLD+hsa_circ_ 0004535 group, as shown by Masson staining (P<0.05). Conclusions The expression of hsa_circ_0004535 and miRNA-1827 play important roles in regulating lipid metabolism, insulin sensitivity, inflammatory pathways, hepatocyte apoptosis, and hepatic fibrosis-related pathways in an animal model of T2DM combined with MAFLD.