Aloesin improves metabolic associated fatty liver disease and obesity by targeting TGFBR1

BACKGROUND Metabolic associated fatty liver disease (MAFLD) is a chronic liver condition with a high global prevalence. Obesity and its associated insulin resistance are among the main risk factors for MAFLD, for which no effective clinical treatments are currently available. Aloesin, a natural chromone compound derived from Aloe vera, has anti-inflammatory, antioxidant, anticancer, and antidiabetes activity. However, its involvement in MAFLD has not been systematically studied. PURPOSE This study investigated the effectiveness of aloesin against MAFLD and obesity and elucidated its potential molecular mechanism. METHODS Aloesin was added to the high-fat diet-of an induced mouse model and to oleic acid/palmitic acid-induced HepG2 cells to explore its effect on lipid metabolism. Molecular targets were identified by reverse docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). RESULTS Aloesin significantly reduced lipid accumulation in hepatocytes in both the high-fat diet-induced MAFLD mouse model and the oleic acid/palmitic acid-induced HepG2 cells. It also alleviated oxidative stress and energy metabolism disorders and decreased the body fat mass in mice fed the high-fat diet, which ameliorated the pathological features of MAFLD and obesity. Target prediction and validation identified TGFBR1 as a direct target of aloesin, which was confirmed by CETSA and DARTS. Functional experiments demonstrated that overexpression of TGFBR1 increased lipid accumulation and metabolic disturbances, which were reversed by aloesin. CONCLUSION Aloesin improved lipid deposition and slowed the progression of MAFLD by targeting TGFBR1. The results support its potential application for the prevention and treatment of MAFLD.