The role of glycolysis in MASLD development: Pathogenesis and therapeutic strategies

Metabolic dysfunction-associated steatotic liver disease (MASLD), as the hepatic manifestation of metabolic syndrome, is characterized by hepatic steatosis, inflammation, and fibrosis. Accumulating evidence suggests that metabolic reprogramming, particularly enhanced glycolysis, plays an important role in the pathogenesis of MASLD. Dysregulated glycolysis not only supplies energy and biosynthetic precursors for multiple hepatic cell types but also directly contributes to lipid accumulation, inflammatory activation, fibrogenesis, and even hepatocellular carcinogenesis. This review summarizes the mechanisms underlying glycolytic reprogramming in MASLD and examines the distinct roles of glycolytic alterations in various cell types, including hepatocytes, macrophages, hepatic stellate cells (HSCs), T cells, and bile duct epithelial cells (BECs). Furthermore, glycolysis mediates the crosstalk between different cell types and organ types in MASLD, modulating cytokine production and activating pro-inflammatory and pro-fibrotic signaling pathways. Finally, this article discusses the potential and challenges of targeting key glycolytic enzymes - such as hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3) and Pyruvate kinase M2 (PKM2) - as therapeutic strategies, offering new perspectives for alleviating the disease burden of MASLD.