Abstract

Type 2 diabetes mellitus (T2DM) poses a major global health challenge due to its considerable disability and mortality rates. The complex etiology of T2DM involves hepatic steatosis and autophagy dysfunction. Previous research indicates that oleanolic acid (OA) ameliorates T2DM, with signal transducer and activator of transcription 3 (STAT3) serving as a crucial regulator in numerous cellular processes. Therefore, this study aims to explore whether the therapeutic effects of OA are associated with STAT3 activation and its potential role in hepatic lipid metabolism and autophagy in T2DM. T2DM was induced in mice by feeding a high‐fat diet followed by multiple low‐dose streptozotocin injections. OA notably lowered blood glucose and lipid levels, along with improvements in glucose tolerance and insulin sensitivity. Additionally, OA alleviated liver injury and steatosis. In T2DM mice, OA reduced hepatic protein and gene expression associated with fatty acid uptake/synthesis while enhancing those linked to fatty acid β‐oxidation. Moreover, OA modulated autophagy‐related proteins, as evidenced by increased p62 levels and decreased LC3‐II and Beclin‐1 levels. Molecular docking analysis predicted a potential interaction between OA and STAT3, and Western blot showed increased STAT3 phosphorylation at Y705 after OA treatment . In vitro, STAT3 inhibition blunted the ability of OA to restore the expression profiles of autophagy and lipid metabolism in insulin‐resistant liver cells. Collectively, OA may ameliorate T2DM via concomitant STAT3 phosphorylation to modulate hepatic lipid metabolism and autophagy. This study offers novel insights into the mechanisms by which OA treats T2DM, presenting fresh perspectives for T2DM clinical management. This study demonstrates that oleanolic acid (OA) may ameliorate type 2 diabetes mellitus (T2DM) by modulating hepatic lipid metabolism and autophagy in a manner concomitant with STAT3 phosphorylation. Specifically, OA downregulates fatty