2. Academic Validation
  3. 3-Hydroxypropionaldehyde modulates tryptophan metabolism to activate AhR signaling and alleviate ethanol-induced liver injury

3-Hydroxypropionaldehyde modulates tryptophan metabolism to activate AhR signaling and alleviate ethanol-induced liver injury

  • Phytomedicine. 2025 Feb 2:139:156445. doi: 10.1016/j.phymed.2025.156445.
Chen Liu 1,  Yi Wang 2,  Linlin Sheng 1,  Yun Zhang 1,  Gang Luo 3,  Xiong Z Ruan 4,  Yaxi Chen 5,  Meizhou Huang 6
Affiliations

Affiliations

  • 1 Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
  • 2 Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, Department of General Surgery (Hepatopancreatobiliary surgery), The Affiliated Hospital, Southwest Medical University, Sichuan, 646000, China.
  • 3 Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
  • 4 Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China. Electronic address: x.ruan@ucl.ac.uk.
  • 5 Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China. Electronic address: chenyaxi@cqmu.edu.cn.
  • 6 Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, Department of General Surgery (Hepatopancreatobiliary surgery), The Affiliated Hospital, Southwest Medical University, Sichuan, 646000, China. Electronic address: 13141254071@163.com.
PMID: 39922148 DOI: 10.1016/j.phymed.2025.156445
Abstract

Background: Although probiotics-based therapies and postbiotics derived from Lactobacillus reuteri (L. reuteri) hold promising potential in mitigating alcohol-associated liver disease (ALD), the role of L. reuteri's metabolite, 3-Hydroxypropionaldehyde (3-HPA, reuterin), remains elusive.

Purpose: The objective of this study is to examine the influence of 3-HPA on the attenuation of alcohol-induced hepatic steatosis and its underlying mechanisms.

Methods: The study utilizes network pharmacology to identify potential targets for 3-HPA in treating ALD. Comprehensive analytical methods, including histological and biochemical assessments, coupled with metabolomics techniques, are employed to evaluate the protective mechanisms and actions of 3-HPA in ALD. Additionally, the therapeutic potential of hepatic Aryl Hydrocarbon Receptor (AhR) activation is explored through using both an AhR agonist and inhibitor, in order to assess the potential of 3-HPA as an AhR ligand in treating ALD.

Results: Chronic alcohol consumption stimulates AhR activation in hepatocytes, both in vivo and in vitro, leading to the disruption of hepatic tryptophan metabolism. Our observations indicate that 3-HPA has the potential to regulate this process by activating AhR signaling through modulating tryptophan metabolism, specifically affecting indole acetaldehyde, indole, and 5‑hydroxy-l-tryptophan (5-HTP) levels. Mechanistically, 3-HPA demonstrates potential as an effective AhR agonist in mitigating ethanol-induced liver injury by regulating AhR-CD36 signaling, thereby exerting protective effects against hepatic steatosis.

Conclusion: Ultimately, the study identifies a previously uncharacterized role of 3-HPA in alleviating alcohol-associated liver injury and hepatic steatosis. It further elucidates that 3-HPA serves as a mediator in tryptophan metabolism, activating the AhR signaling, thereby suggesting its potential as a promising candidate for the treatment of ALD.

Keywords

3-Hydroxypropionaldehyde; AhR signaling; Alcohol-associated liver disease; Hepatic steaotsis; Tryptophan metabolism.

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