Diosgenin Ameliorates Insulin Resistance in High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease Rats via the Adiponectin/ADIPOR1/APPL1 Pathway.

Insulin resistance (IR) is a central pathogenic driver of metabolic dysfunction-associated steatotic liver disease (MASLD), yet current therapeutic strategies remain insufficient. Diosgenin (DG), a well-characterized natural compound, has been reported to modulate IR-related mechanisms and, thus, holds significant promise for MASLD treatment. In this study, rodent models fed a high-fat diet and HepG2 cells treated with free fatty acids were employed to simultaneously evaluate systemic metabolic outcomes (including hepatic indices and glucose tolerance) and cellular responses (including lipid accumulation and glucose uptake). The findings demonstrate that DG activates the ADIPOR1/APPL1 signaling pathway by elevating circulating adiponectin levels, thereby enhancing GLUT4-dependent glucose uptake, suppressing key gluconeogenic enzymes (PEPCK and G6 Pase), and inhibiting de novo lipogenesis through SREBP-1 downregulation. These mechanistic insights reveal that DG mitigates IR by augmenting adiponectin signaling, thereby providing a scientific basis for the development of phytotherapeutic strategies targeting MASLD.