Dual Targeting of Alcohol Use Disorder and Alcohol–Associated Liver Disease: Emerging Molecular Targets Along the Gut–Liver–Brain Axis

Alcohol–associated liver disease (ALD) is the hepatic end of alcohol use disorder (AUD), yet only abstinence and transplantation modify it, and recent liver-only programmes in alcohol–associated hepatitis have not delivered. This review asks whether the receptors, ligands and transporters setting drinking behaviour and alcohol-related liver injury are largely one set along the gut–liver–brain axis, so one molecule could lower both. Where resolved, it is cell-specific: hepatic glucagon-like peptide-1 receptor sits, in non-alcohol models, on sinusoidal endothelial and CD8+ T cells, not hepatocytes, and ethanol induces hepatocyte fibroblast growth factor 21, whose analogue acts on β-Klotho+ amygdala neurons. Organised by target, not organ, each candidate is appraised separately on both sides, negatives, terminations and non-replications counting alike. Of sixteen targets spanning incretin, hepatokine, glutamatergic and microbial or neuroimmune families, three are supported on both sides in the desired direction but only in separate experiments, three point in opposite directions, and ten have had no manipulation read out on both; for none were both organs read out in one experiment. Dual targeting changes what trials must measure: only one of 64 registered trials makes both endpoints primary, so objectively measured intake and a liver endpoint must be co-primary.