Dysregulation of the AMPK-SREBP1-FASN axis in MASLD: driving a vicious cycle of lipotoxicity and metabolic-immune crosstalk

Metabolic dysfunction-associated steatotic liver disease (MASLD), whose pathogenesis involves complex multi-organ crosstalk and the remodeling of the hepatic immune microenvironment, constitutes a major global health challenge. The latest research indicates that the dysregulation of the AMPK-SREBP1-FASN (ASF) signaling axis plays a core role in mediating abnormal fatty acid synthesis and the accumulation of lipotoxic metabolites in MASLD, serving as a key molecular hub linking hepatic metabolic disorders with immune inflammatory responses. Dysregulated ASF axis and the subsequent lipotoxic products not only directly impair hepatocellular organelle function but also, by disrupting intercellular communication and reprogramming immune cell and hepatocyte metabolism, drive a self-perpetuating “metabolic-immune” vicious cycle. This cycle propels disease progression toward fibrosis and extrahepatic complications. However, how ASF axis dysregulation specifically reshapes the hepatic immune landscape remains to be systematically elucidated. This review aims to systematically describe the crucial role of the ASF axis in MASLD. First, it outlines the pivotal function of this axis in multi-system interactions and the disruption of the hepatic immune microenvironment. It then provides an in-depth analysis of the regulatory mechanisms and functional characteristics of the ASF axis in both hepatocytes and immune cells. Furthermore, it explores the molecular mechanisms by which ASF axis dysregulation exacerbates lipotoxicity through promoting CD36-dependent lipid uptake and dissects how lipotoxicity impairs hepatocellular function and hepatic immune homeostasis in MASLD. Finally, the review summarizes potential therapeutic strategies targeting the ASF axis, which are designed to disrupt the metabolic-immune vicious cycle and restore systemic homeostasis. By offering an integrated perspective, this review seeks to advance the understanding of the immune-metabolic pathogenesis of MASLD and to establish a theoretical foundation for developing precise therapeutic interventions.