Roles of short-chain fatty acids in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, affecting more than 30% of adults and 7%-14% of youths globally. MASLD and its advanced form of metabolic dysfunction-associated steatohepatitis (MASH) can progress to liver cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective therapies for MASLD and MASH remain limited. Accumulating evidence indicates that short-chain fatty acids (SCFAs) modulate the activation of hepatic innate and adaptive immune cells, influencing liver inflammation and fibrosis. Moreover, SCFAs modulate liver lipid and glucose metabolism and insulin sensitivity, affecting MASLD progression. This review summarizes the cellular and molecular mechanisms through which SCFAs impact liver inflammation, fibrosis, and energy metabolism. Several key molecular signaling pathways are discussed. Clinical trials aiming to modulate SCFA production through different treatments are reviewed. Collectively, emerging evidence supports that targeting SCFA-mediated function represents a promising therapeutic strategy for MASLD and MASH.