Ginseng-derived exosome-like nanovesicles protect against liver fibrosis by regulating TIMP2 pathways and gut dysbiosis.

Metabolic dysfunction-associated fatty liver disease (MASLD) and alcohol-associated liver disease (ALD) are prevalent chronic liver diseases that can progress to steatohepatitis, fibrosis, cirrhosis, and ultimately liver failure. Here, we demonstrated that oral administration of GNVs provided substantial protection against liver injury and fibrosis in MASLD and ALD mouse models. In a Western-style high-fat diet-induced MASLD model and a chronic binge alcohol-induced ALD model, GNVs treatment significantly reduced gut leakiness by restoring intestinal junctional complex proteins and rebalancing the gut microbiome. GNVs attenuated hepatic lipid accumulation, oxidative stress and fibrogenic markers. GNV treatment downregulated the fibrosis-associated tissue inhibitor of metalloproteinase-2 (TIMP2) pathway in hepatic stellate cells, which is linked to enhanced matrix degradation and reduced fibrogenesis. GNVs prevent MASLD- and ALD-associated gut barrier dysfunction and liver fibrosis through modulation of the gut-liver axis and the TIMP2 pathway. Edible GNVs represent a novel, multifaceted therapeutic strategy for managing chronic liver diseases.