Metabolic drivers of MASLD and MASH: from hormonal imbalance to fibrosis

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe and aggressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent liver-specific consequences of systemic metabolic dysfunction. This review synthesises current evidence on the metabolic and hormonal determinants of MASLD progression, with a particular focus on the mechanisms linking systemic dysfunction across multiple tissues to hepatic inflammation and fibrosis. MASLD pathogenesis is driven by complex interactions between insulin resistance, impaired glucose metabolism, dysfunctional adipose tissue lipolysis and altered hepatic de novo lipogenesis. Central to this process is the dysregulation of key metabolic hormones, including insulin and glucagon, whose imbalance disrupts both glucose and lipid fluxes, leading not only to hepatic steatosis but also to altered hepatic glucose handling, increased substrate delivery and reduced metabolic flexibility. This promotes lipid accumulation as well as glucotoxic and lipotoxic stress. These metabolic disturbances trigger hepatocellular injury and activate inflammatory signalling pathways, including adipokine-mediated crosstalk between adipose tissue and the liver, promoting hepatic stellate cell activation and ultimately leading to a state of chronic low-grade inflammation (metaflammation) that integrates hepatocyte stress, immune cell activation and hepatic stellate cell-driven fibrogenesis. This review also highlights sex-specific hormonal regulation and the gut-liver-adipose axis as determinants of disease heterogeneity and immunometabolic injury. By integrating mechanistic insights across glucose and lipid metabolism, tissues and hormonal pathways, this review underscores how systemic metabolic dysfunction is translated into progressive liver injury and fibrosis. Understanding these interconnected mechanisms of disease progression is essential for identifying therapeutic targets and advancing mechanism-based and precision medicine approaches for MASLD and MASH.