New Insights into AMPK, as a Potential Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease and Hepatic Fibrosis.

AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.