This review aims to systematically describe the expression and structural characteristics of AMPK, thoroughly discuss the regulatory mechanisms of AMPK in lipid metabolism, inflammatory response, cell apoptosis, and fibrosis in MASLD based on recent research advances, and summarize the progress and challenges of AMPK activators in preclinical and clinical studies, thereby providing theoretical basis for developing therapeutic strategies for MASLD. The gene discussed is PRKAA1; the disease is metabolic dysfunction-associated steatotic liver disease.