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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

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

  • Tom Ryu1
  • Beom Sun Chung2
  • Keungmo Yang3
  1. 1Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul 04401, Republic of Korea
  2. 2Department of Anatomy, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
  3. 3Department of Internal Medicine, Division of Gastroenterology and Hepatology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{ryu2026dual,
  title = {{Dual Targeting of Alcohol Use Disorder and Alcohol–Associated Liver Disease: Emerging Molecular Targets Along the Gut–Liver–Brain Axis}},
  author = {Tom Ryu and Beom Sun Chung and Keungmo Yang},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = nov,
  doi = {10.3390/ijms27219921},
  url = {https://www.mdpi.com/1422-0067/27/21/9921},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Dual Targeting of Alcohol Use Disorder and Alcohol–Associated Liver Disease: Emerging Molecular Targets Along the Gut–Liver–Brain Axis
AU  - Tom Ryu
AU  - Beom Sun Chung
AU  - Keungmo Yang
PY  - 2026
DA  - 2026/11/05
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219921
UR  - https://www.mdpi.com/1422-0067/27/21/9921
AB  - 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.
SN  - 1422-0067
ER  -