Betaine in Metabolic Dysfunction-Associated Steatotic Liver Disease: Mechanisms of Action and Therapeutic Potential.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and a leading cause of advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The disease develops through the interaction of multiple interconnected pathophysiological mechanisms, including insulin resistance, dysregulated lipid metabolism, oxidative stress, mitochondrial and endoplasmic reticulum dysfunction, chronic inflammation, gut-liver axis disruption, and progressive fibrogenesis. Betaine, a naturally occurring methyl donor, has been investigated as a potential therapeutic agent because of its diverse metabolic and cytoprotective effects. This review summarizes current knowledge on the mechanisms by which betaine may influence MASLD development and progression. Preclinical studies indicate that betaine improves insulin sensitivity and hepatic lipid homeostasis, reduces oxidative and endoplasmic reticulum stress, preserves mitochondrial function, mitigates inflammatory signaling, and limits hepatic fibrosis. In addition, growing evidence suggests that betaine contributes to the maintenance of gut-liver axis homeostasis, further supporting its beneficial effects on liver function. Although these findings are consistent across preclinical models, clinical evidence remains limited, and the therapeutic efficacy of betaine in patients with MASLD has not yet been established. Further well-designed clinical trials are required to determine its clinical value, optimal therapeutic strategy, and potential role in the management of MASLD.