Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Kv1.3 knockdown attenuates alcohol-related liver injury in mice through induction of tryptamine

Acta Pharmacologica Sinica volume 46, pages 2963–2974 (2025)Cite this article

Abstract

Alcohol-related liver disease (ALD) refers to a spectrum of liver diseases caused by chronic or acute excessive alcohol consumption. Excess alcohol consumption and dysregulated immunometabolism are the major contributors to the disease progression. The pathogenesis of ALD remains unclear with macrophage activity playing a key role in disease development. Kv1.3 potassium channel is essential for the regulation of macrophage function. In this study, we investigated whether Kv1.3 channels influenced the progression of ALD by modulating macrophage function. A murine model of ALD was established in male mice. We showed that Kv1.3 knockdown significantly attenuated alcohol-induced liver injury, lipid deposition, and inflammatory responses in ALD mice. Metabolomic analysis revealed that Kv1.3 knockdown significantly increased the levels of tryptamine, a tryptophan metabolite, in the liver of ALD mice. During the last 5 days of the EtOH feeding period, injection of exogenous tryptamine (1, 10, 20 mg·kg−1·d−1, i.p.) notably alleviated ethanol-induced liver steatosis and inflammation in ALD mice. In LPS-challenged RAW264.7 cells, tryptamine (62.5, 125, 250 μM) dose-dependently suppressed the secretion of pro-inflammatory cytokines IL-6, IL-1β and TNF-α. RNA-seq analysis of RAW264.7 cells revealed that tryptamine treatment significantly altered Toll-like receptor and NF-κB signaling pathways. We conclude that in the ALD mice, Kv1.3 negatively regulates tryptamine levels, which inhibits macrophage activation and reduces the inflammatory responses through the TLR4/NF-κB signaling pathway. Our results offer new targets and intervention strategies for the prevention and treatment of ALD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Alcohol exposure upregulates Kv1.3 expression in vivo.
Fig. 2: Knockdown of Kv1.3 inhibits alcohol-related liver injury in mice.
Fig. 3: Kv1.3 deficiency increases tryptamine in the liver.
Fig. 4: Tryptamine exposure modulates ALD in mice.
Fig. 5: Tryptamine modulates inflammation in vitro.
Fig. 6: Transcriptomic analysis reveals the mechanism of tryptamine intervention in ETOH+LPS-induced RAW264.7 cells.
Fig. 7: Tryptamine reduces inflammation via the TLR4/NF-κB signaling pathway.

Similar content being viewed by others

References

  1. Åberg F, Jiang ZG, Cortez-Pinto H, Männistö V. Alcohol-associated liver disease-Global epidemiology. Hepatology. 2024;80:1307–22.

  2. Leggio L, Lee MR. Treatment of alcohol use disorder in patients with alcoholic liver disease. Am J Med. 2017;130:124–34.

    Article  PubMed  Google Scholar 

  3. Mackowiak B, Fu Y, Maccioni L, Gao B. Alcohol-associated liver disease. J Clin Invest. 2024;134:e176345.

  4. Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol. 2015;12:231–42.

    Article  PubMed  Google Scholar 

  5. Gao H, Jiang Y, Zeng G, Huda N, Thoudam T, Yang Z, et al. Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease. eGastroenterology. 2024;2:e100104.

  6. Ambade A, Lowe P, Kodys K, Catalano D, Gyongyosi B, Cho Y, et al. Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis, and inflammation in mice. Hepatology. 2019;69:1105–21.

    Article  CAS  PubMed  Google Scholar 

  7. Marin V, Poulsen K, Odena G, McMullen MR, Altamirano J, Sancho-Bru P, et al. Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients. J Hepatol. 2017;67:1018–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang M, Shen G, Xu L, Liu X, Brown JM, Feng D, et al. IL-1 receptor-like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages. J Hepatol. 2017;S0168-8278:32263–8.

  9. Wu X, Fan X, McMullen MR, Miyata T, Kim A, Pathak V, et al. Macrophage-derived MLKL in alcohol-associated liver disease: regulation of phagocytosis. Hepatology. 2023;77:902–19.

    Article  PubMed  Google Scholar 

  10. Van den Bossche J, O’Neill LA, Menon D. Macrophage immunometabolism: where are we (going)? Trends Immunol. 2017;38:395–406.

    Article  PubMed  Google Scholar 

  11. Liu J, Lv XW, Zhang L, Wang H, Li J, Wu B. Review on biological characteristics of Kv1.3 and its role in liver diseases. Front Pharmacol. 2021;12:652508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Selvakumar P, Fernández-Mariño AI, Khanra N, He C, Paquette AJ, Wang B, et al. Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators. Nat Commun. 2022;13:3854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. DeCoursey TE, Chandy KG, Gupta S, Cahalan MD. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis? Nature. 1984;307:465–8.

    Article  CAS  PubMed  Google Scholar 

  14. Upadhyay SK, Eckel-Mahan KL, Mirbolooki MR, Tjong I, Griffey SM, Schmunk G, et al. Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance. Proc Natl Acad Sci USA. 2013;110:E2239–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee WH, Najjar SM, Kahn CR, Hinds TD Jr. Hepatic insulin receptor: new views on the mechanisms of liver disease. Metabolism. 2023;145:155607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Man S, Deng Y, Ma Y, Fu J, Bao H, Yu C, et al. Prevalence of liver steatosis and fibrosis in the general population and various high-risk populations: a nationwide study with 5.7 million adults in China. Gastroenterology. 2023;165:1025–40.

    Article  PubMed  Google Scholar 

  17. Gao B, Xu MJ, Bertola A, Wang H, Zhou Z, Liangpunsakul S. Animal models of alcoholic liver disease: pathogenesis and clinical relevance. Gene Expr. 2017;17:173–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sougioultzis S, Dalakas E, Hayes PC, Plevris JN. Alcoholic hepatitis: from pathogenesis to treatment. Curr Med Res Opin. 2005;21:1337–46.

    Article  CAS  PubMed  Google Scholar 

  19. Dhanda AD, Collins PL, McCune CA. Is liver biopsy necessary in the management of alcoholic hepatitis? World J Gastroenterol. 2013;19:7825–9.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Navarro-Pérez M, Capera J, Benavente-Garcia A, Cassinelli S, Colomer-Molera M, Felipe A. Kv1.3 in the spotlight for treating immune diseases. Expert Opin Ther Targets. 2024;28:67–82.

    Article  PubMed  Google Scholar 

  21. Cheng S, Jiang D, Lan X, Liu K, Fan C. Voltage-gated potassium channel 1.3: a promising molecular target in multiple disease therapy. Biomed Pharmacother. 2024;175:116651.

    Article  CAS  PubMed  Google Scholar 

  22. Wu B, Liu JD, Bian E, Hu W, Huang C, Meng X, et al. Blockage of Kv1.3 regulates macrophage migration in acute liver injury by targeting δ-catenin through RhoA signaling. Int J Biol Sci. 2020;16:671–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu BM, Liu JD, Li YH, Li J. Margatoxin mitigates CCl4‑induced hepatic fibrosis in mice via macrophage polarization, cytokine secretion, and STAT signaling. Int J Mol Med. 2020;45:103–14.

    CAS  PubMed  Google Scholar 

  24. O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–65.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ayres JS. Immunometabolism of infections. Nat Rev Immunol. 2020;20:79–80.

    Article  CAS  PubMed  Google Scholar 

  26. Makowski L, Chaib M, Rathmell JC. Immunometabolism: from basic mechanisms to translation. Immunol Rev. 2020;295:5–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Buck MD, Sowell RT, Kaech SM, Pearce EL. Metabolic instruction of immunity. Cell. 2017;169:570–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ravishankar B, Liu H, Shinde R, Chandler P, Baban B, Tanaka M, et al. Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci USA. 2012;109:3909–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Krishnan S, Ding Y, Saedi N, Choi M, Sridharan GV, Sherr DH, et al. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep. 2018;23:1099–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Agista AZ, Tanuseputero SA, Koseki T, Ardiansyah, Budijanto S, Sultana H, et al. Tryptamine, a microbial metabolite in fermented rice bran suppressed lipopolysaccharide-induced inflammation in a murine macrophage model. Int J Mol Sci. 2022;23:11209.

  31. Williams BB, Van Benschoten AH, Cimermancic P, Donia MS, Zimmermann M, Taketani M, et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014;16:495–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhai L, Xiao H, Lin C, Wong HLX, Lam YY, Gong M, et al. Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome. Nat Commun. 2023;14:4986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the Natural Science Foundation of Anhui Province (grant no. 2108085MH257), Anhui Medical University (Scientific Research Platform Improvement Project of Anhui Medical University (2023xkjT061)), and Research Fund of Anhui Institute of translational medicine (grant no. 2023zhyx-B11). The authors thank BGI Tech Solutions Co., Ltd. and LC-BioTechnology Co., Ltd. (Hangzhou, China) for technical support. The authors also thank LetPub for linguistic assistance during the preparation of this manuscript.

Author information

Author notes

  1. These authors contributed equally: Hao Wang, Guo-qing Xia, Ting Ke

Authors and Affiliations

  1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China

    Hao Wang, Guo-qing Xia, Ting Ke, Xi-xi Chen, Wen-jun Zhen, Yuan-yuan Tian, Shi Chen, Cheng Zhang, Jun Li, Lei Zhang, Wen-fang Tian & Bao-ming Wu

  2. School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    Hao Wang, Guo-qing Xia, Ting Ke, Xi-xi Chen, Wen-jun Zhen, Yuan-yuan Tian, Shi Chen, Cheng Zhang, Jun Li, Lei Zhang, Wen-fang Tian & Bao-ming Wu

  3. Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China

    De-jun Wu & Liang He

  4. Department of Gastroenterology, The First Affiliated Hospital of USTC, Hefei, 230001, China

    Ye-tao Wang

Authors
  1. Hao Wang
    View author publications

    Search author on:PubMed Google Scholar

  2. Guo-qing Xia
    View author publications

    Search author on:PubMed Google Scholar

  3. Ting Ke
    View author publications

    Search author on:PubMed Google Scholar

  4. Xi-xi Chen
    View author publications

    Search author on:PubMed Google Scholar

  5. Wen-jun Zhen
    View author publications

    Search author on:PubMed Google Scholar

  6. Yuan-yuan Tian
    View author publications

    Search author on:PubMed Google Scholar

  7. Shi Chen
    View author publications

    Search author on:PubMed Google Scholar

  8. Cheng Zhang
    View author publications

    Search author on:PubMed Google Scholar

  9. Jun Li
    View author publications

    Search author on:PubMed Google Scholar

  10. Lei Zhang
    View author publications

    Search author on:PubMed Google Scholar

  11. De-jun Wu
    View author publications

    Search author on:PubMed Google Scholar

  12. Ye-tao Wang
    View author publications

    Search author on:PubMed Google Scholar

  13. Liang He
    View author publications

    Search author on:PubMed Google Scholar

  14. Wen-fang Tian
    View author publications

    Search author on:PubMed Google Scholar

  15. Bao-ming Wu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

BMW, WFT, and LH Conceived and designed the experiments, HW, GQX, TK, and LH Performed the experiments, XXC and WJZ performed the data analyzes and wrote the paper, YYT, SC, CZ, JL, LZ, YTW, DJW helped perform the analysis with constructive discussions.

Corresponding authors

Correspondence to Liang He, Wen-fang Tian or Bao-ming Wu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, H., Xia, Gq., Ke, T. et al. Kv1.3 knockdown attenuates alcohol-related liver injury in mice through induction of tryptamine. Acta Pharmacol Sin 46, 2963–2974 (2025). https://doi.org/10.1038/s41401-025-01544-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41401-025-01544-4

Keywords

Search

Advanced search

Quick links