A Unified Mechanistic Framework for Metabolism-Based Therapeutics in MASH: A Comprehensive Review of SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Statins

Metabolic dysfunction-associated steatohepatitis (MASH) represents a multifaceted and progressive hepatic disorder that poses considerable therapeutic challenges in contemporary clinical practice. The therapeutic landscape has undergone substantial transformation with the identification of three pharmacologically distinct classes of metabolism-targeting agents, sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), each demonstrating remarkable anti-fibrotic efficacy. However, this breakthrough has simultaneously presented an intriguing mechanistic conundrum: how do these therapeutically disparate compounds achieve their shared objective of hepatic fibrosis resolution?This comprehensive review endeavors to construct an integrative theoretical framework addressing this fundamental question. We hypothesize that adenosine monophosphate-activated protein kinase (AMPK), functioning as the cellular energy homeostasis sentinel, constitutes the primary convergence point for these therapeutic interventions. Our proposed model suggests that each pharmacological class engages this central hub through distinct, non-redundant upstream signaling cascades: SGLT2 inhibitors operate through direct LKB1-dependent metabolic perturbation, effectively creating an "energy deficit state"; GLP-1 receptor agonists function via receptor-mediated CaMKKβ-dependent "endocrine signaling pathways"; while statins exert their effects through isoprenoid depletion-mediated "metabolic stress responses."This mechanistic divergence subsequently generates differential yet synergistic downstream cellular responses. Additionally, we present a comprehensive multi-phase paradigm explaining the seemingly contradictory upregulation of SGLT2 expression within fibrotic hepatic tissue. This model encompasses an initial liver-specific "compensatory adaptation" occurring in hepatocytes and liver sinusoidal endothelial cells, subsequently followed by pathological "epigenetic stabilization" in activated hepatic stellate cells mediated through the hypoxia-inducible factor-1α (HIF-1α) and brahma-related gene 1 (BRG1) chromatin remodeling machinery.This unifying theoretical construct not only addresses existing mechanistic inconsistencies but also establishes a robust foundation for future MASH therapeutic development, particularly emphasizing personalized treatment approaches and rationally designed combination therapy strategies.