Transforming Growth Factor-β Signaling in Alcohol-Associated Liver Disease: A Multicellular Perspective.

Transforming growth factor-β (TGF-β) signaling exerts broad regulatory n effects on alcohol-associated liver disease (ALD) progression influencing processes such as hepatocellular injury, regeneration, inflammation, fibrogenesis, cirrhosis, carcinogenesis, and hepatic failure. TGF-β modifies alcohol-induced signals in multiple liver-resident cell types, including hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and immune populations, particularly macrophages. To delinieate its context-specific roles in ALD, 172 of 421 PubMed-listed publications (2000 to 2025, search terms "TGF-β" AND "alcohol" AND "liver disease") were reviewed, supplemented by 18 foundational studies published before. In hepatocytes, TGF-β promotes oxidative stress, apoptosis, metabolic reprogramming, and epithelial-to-mesenchymal transition. In HSCs and Kupffer cells (KCs), gut-derived endotoxins, ethanol, and unsaturated fatty acids induce TGF-β alongside proinflammatory cytokines. Ethanol metabolism generates acetaldehyde, which drives TGF-β and receptor expression, enhances canonical and non-canonical signaling, and engages epigenetic regulators to promote extracellular matrix deposition. In LSECs, alcohol-induced TGF-β suppresses proliferation, contributing to sinusoidal capillarization, impaired endothelial regeneration, and fibrogenesis. TGF-β dampens clearance of damaged hepatocytes and perpetuating chronic injury by suppressing natural killer cell cytotoxicity and promoting regulatory T cell differentiation. At end-stage disease, TGF-β promotes expansion and fate-switching of cholangiocyte-derived liver progenitor cells to replenish lost hepatocytes. Despite its central role in ALD, therapeutic exploitation of TGF-β signaling remains underexplored. Future studies should define cell type-specific signaling nodes to enable precision therapies.