Metabolic Drivers of MASLD and MASH: Diabetologia | June 2026

Introduction:

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are now recognized as systemic metabolic diseases rather than isolated liver disorders. This review integrates current knowledge on how hormonal, metabolic, inflammatory, and fibrotic pathways interact to drive disease progression.

Why was this review needed?

Despite major advances in understanding MASLD, the mechanisms linking obesity, insulin resistance, adipose dysfunction, and chronic inflammation to progressive liver fibrosis remain incompletely integrated. A comprehensive understanding is essential for developing precision therapies.

What did the review show?

• Insulin resistance is the central metabolic driver of MASLD and MASH progression.
• Dysfunctional adipose tissue increases free fatty acid delivery to the liver, promoting hepatic steatosis and lipotoxicity.
• Imbalance between insulin and glucagon disrupts glucose and lipid metabolism, accelerating liver injury.
• Chronic glucotoxicity and lipotoxicity trigger hepatocyte injury and persistent low-grade inflammation (metaflammation).
• Crosstalk between adipose tissue, the gut, and the liver amplifies immune activation and disease progression.
• Activation of hepatic stellate cells is the key pathway leading to liver fibrosis.
• Sex hormones and the gut–liver–adipose axis contribute to disease heterogeneity and individual susceptibility.
• The review highlights multiple therapeutic targets across metabolic, hormonal, inflammatory, and fibrotic pathways.

Clinical Impact:

MASLD should be managed as a multisystem metabolic disease rather than a liver-specific disorder. Targeting insulin resistance, adipose dysfunction, hormonal imbalance, and chronic inflammation may help prevent progression to MASH and advanced fibrosis.

Take-Home Message:

MASLD and MASH result from complex interactions between metabolic dysfunction, hormonal imbalance, inflammation, and fibrosis. Understanding these interconnected pathways provides the foundation for precision medicine and the development of mechanism-based therapies that target disease progression rather than hepatic steatosis alone.