Research Progress on AMPK in the Pathogenesis and Treatment of MASLD

Feng Jiang ^* Li Menghuan Tingting Yao Xuejie Yi HaiNing Gao ^*

• Shenyang Sport University, Shenyang, China

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as non-alcoholic fatty liver disease, NAFLD) has become one of the most prevalent chronic liver diseases worldwide, with its incidence continuously rising alongside the epidemic of metabolic disorders. AMP-activated protein kinase (AMPK), as a key regulator of cellular energy metabolism, influences multiple pathological processes associated with MASLD. This review systematically summarizes the regulatory roles of AMPK in lipid metabolism, inflammatory response, cell apoptosis, and fibrosis. Additionally, it discusses the latest developments of AMPK activators from preclinical to clinical studies, while analyzing the major challenges currently faced and potential strategies for resolution. A deeper understanding of AMPK regulatory mechanisms will contribute to the development of more effective therapeutic approaches for MASLD. the context of MASLD, hepatic AMPK activity is significantly reduced, while AMPK activation can ameliorate multiple pathological processes including lipid metabolism, inflammatory response, and fibrosis (7). Although preclinical studies have generally demonstrated the therapeutic potential of AMPK activators for MASLD, existing AMPK activators have not achieved the expected therapeutic efficacy in clinical trials, facing challenges in clinical translation (8). Moreover, the roles of AMPK at different pathological stages remain incompletely elucidated (7, 9). Therefore, developing therapeutic strategies that precisely modulate the AMPK signaling pathway through a deeper understanding of AMPK regulatory mechanisms holds significant importance for expanding treatment options for MASLD. 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.