Vagal blockade of the brain-liver axis deters cancer-associated cachexia

Aliesha Garrett¹, Naama Darzi², Ashlesha Deshmukh³, Nataly Rosenfeld², Omer Goldman², Lital Adler², Elizabeta Bab-Dinitz², Oded Singer⁴, Alireza Hassani Najafabadi⁵, Chi Wut Wong⁶, Shree Bose⁷, Peggy M Randon⁸, Francisco Bustamante⁵, Rene Larios⁵, Alexander Brandis⁴, Tevie Mehlman⁴, Brandon Smaglo⁶, Ping Chang⁶, Jacqueline Oliva⁹, Cara Haymaker⁹, Laukik Nagawekar¹⁰, Sophie R Wu¹¹, Yixuan Huang¹², Aidan Shen⁵, Ahana Vora⁵, Jon Floyd Padilla⁵, Alissa Pfeffer⁵, Gary Sutherland¹³, Mark Starr¹⁴, Teresa Zimmers¹⁵, Yangzhi Zhu⁵, James Morizio¹⁶, Ayelet Erez¹⁷, Xiling Shen¹⁸

Affiliations

¹ Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA; Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
³ Department of Electrical and Computer Engineering, Duke University, Durham, NC 27708, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁴ Department of Life Science Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel.
⁵ Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA.
⁶ Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Internal Medicine, University of Chicago, Chicago, IL 60637, USA.
⁸ Medical Scientist Training Program, Vanderbilt University Medical School, Nashville, TN 37235, USA.
⁹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Clinical Engineering and Applied Research, Abbot Laboratories, Sylmar, CA 91342, USA.
¹¹ Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
¹² Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.
¹³ Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
¹⁴ Department of Medicine, Duke University, Durham, NC 27708, USA.
¹⁵ Department of Cell, Developmental and Cancer Biology, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
¹⁶ Department of Electrical and Computer Engineering, Duke University, Durham, NC 27708, USA.
¹⁷ Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel. Electronic address: ayelet.erez@weizmann.ac.il.
¹⁸ Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA; Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: xshen3@mdanderson.org.

PMID: 40780194
PMCID: PMC12370180 (available on 2026-08-07)
DOI: 10.1016/j.cell.2025.07.016

Vagal blockade of the brain-liver axis deters cancer-associated cachexia

Aliesha Garrett et al. Cell. 2025.

. 2025 Oct 16;188(21):6044-6063.e24.

doi: 10.1016/j.cell.2025.07.016. Epub 2025 Aug 7.

Authors

Affiliations

¹ Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA; Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
³ Department of Electrical and Computer Engineering, Duke University, Durham, NC 27708, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁴ Department of Life Science Core Facilities, Weizmann Institute of Science, 7610001 Rehovot, Israel.
⁵ Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA.
⁶ Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Internal Medicine, University of Chicago, Chicago, IL 60637, USA.
⁸ Medical Scientist Training Program, Vanderbilt University Medical School, Nashville, TN 37235, USA.
⁹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Clinical Engineering and Applied Research, Abbot Laboratories, Sylmar, CA 91342, USA.
¹¹ Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
¹² Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.
¹³ Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
¹⁴ Department of Medicine, Duke University, Durham, NC 27708, USA.
¹⁵ Department of Cell, Developmental and Cancer Biology, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
¹⁶ Department of Electrical and Computer Engineering, Duke University, Durham, NC 27708, USA.
¹⁷ Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel. Electronic address: ayelet.erez@weizmann.ac.il.
¹⁸ Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA; Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: xshen3@mdanderson.org.

PMID: 40780194
PMCID: PMC12370180 (available on 2026-08-07)
DOI: 10.1016/j.cell.2025.07.016

Abstract

Cancer-associated cachexia (CAC) is a multifactorial and currently incurable syndrome responsible for nearly one-third of cancer-related deaths. It contributes to therapy resistance and increases mortality among affected patients. In this study, we show that cancer-induced systemic inflammation alters vagal tone in CAC mouse models. This vagal dysregulation disrupts the brain-liver vagal axis, leading to a reprogramming of hepatic protein metabolism through the depletion of HNF4α, a key transcriptional regulator of liver function. The loss of HNF4α disrupts hepatic metabolism and promotes systemic inflammation, resulting in cachectic phenotypes. Interventions targeting the right cervical vagus nerve surgically, chemically, electrically, or through a non-invasive transcutaneous device attenuate CAC progression, alleviate its clinical manifestations, and synergize with chemotherapy to improve overall health and survival in mice.

Keywords: HNF4α; cancer-associated cachexia; liver; metabolism; neuromodulation; vagus nerve.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests Duke University and the Weizmann Institute of Science have applied for a patent on the use of this strategy to treat CAC. A.G. and X.S. are co-founders of OnVagus, Inc., a company that is pursuing this strategy to treat CAC.

References

1. Carson MA, Reid J, Hill L, Dixon L, Donnelly P, Slater P, Hill A, and Fitzsimons D (2019). An exploration of the prevalence and experience of cardiac cachexia: protocol for a mixed methods cross-sectional study. BMC Palliat Care 18, 82. 10.1186/s12904-019-0471-0. - DOI - PMC - PubMed
1. Baracos VE, Martin L, Korc M, Guttridge DC, and Fearon KCH (2018). Cancer-associated cachexia. Nature Reviews Disease Primers 4, 17105. 10.1038/nrdp.2017.105. - DOI - PubMed
1. Dhanapal R, Saraswathi T, and Rajkumar N (2011). Cancer cachexia. Journal of Oral and Maxillofacial Pathology 15, 257–260. 10.4103/0973-029x.86670. - DOI - PMC - PubMed
1. von Haehling S, Anker MS, and Anker SD (2016). Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016. Journal of cachexia, sarcopenia and muscle 7, 507–509. 10.1002/jcsm.12167. - DOI - PMC - PubMed
1. da Rocha IMG, Marcadenti A, de Medeiros GOC, Bezerra RA, Rego JFM, Gonzalez MC, and Fayh APT (2019). Is cachexia associated with chemotherapy toxicities in gastrointestinal cancer patients? A prospective study. Journal of cachexia, sarcopenia and muscle 10, 445–454. 10.1002/jcsm.12391. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Vagal blockade of the brain-liver axis deters cancer-associated cachexia

Affiliations

Vagal blockade of the brain-liver axis deters cancer-associated cachexia

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical