Abstract SY09-01: Targeting the vagal gut-brain axis: A new approach to combat cachexia

Abstract Cancer-associated cachexia is a complex, incurable syndrome responsible for nearly one-third of cancer-related deaths, driving therapy resistance and increasing mortality in affected patients. In this study, we identify altered vagal tone as a consequence of cancer-induced systemic inflammation in cachectic animal models. This vagal dysregulation disrupts the liver-brain vagal axis, leading to the rewiring of liver protein metabolism through the depletion of HNF4α, a key regulator of liver function. Notably, downregulation of liver HNF4α in wildtype mice induces cachectic phenotypes. Blocking the right cervical vagus nerve—whether through surgical, chemical, or electrical means, including a non-invasive transcutaneous device—slows cachectic progression, mitigates its manifestations, and enhances chemotherapy efficacy, ultimately improving overall well-being and survival. Additionally, this transcutaneous device effectively inhibits vagal hyperactivity in porcine models and humans, paving the way for an upcoming clinical trial to combat cachexia progression in pancreatic cancer patients. Citation Format: Xiling Shen. Targeting the vagal gut-brain axis: A new approach to combat cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY09-01.