2. Academic Validation
  3. JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake

JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake

  • bioRxiv. 2025 Oct 22:2025.10.21.683287. doi: 10.1101/2025.10.21.683287.
Ezequiel Dantas 1 2,  Anirudh Murthy 2,  Jeshua Kim 1,  Tanvir Ahmed 2,  Mujmmail Ahmed 2,  Tiffany Perrier 2,  Shakti Ramsamooj 2,  Isaac Nathoo 1 2 3,  Lucas Kniess Debarba 1 2,  Andre Lima Queiroz 2,  Shiri Li 2 4,  Baran Ersoy 2,  Miriam Ferrer 5,  Ido Goldstein 6,  Jonathan Gao 1,  Tiffany Lam 7,  Matthew Nagler 7,  Murtaza Malbari 8,  Nasser Altorki 8,  Eduardo Cararo Lopes 9,  Maria Gomez Jenkins 9,  Trishna Das 9,  Mariam Jamal-Hanjani 10,  Eileen White 9,  Tobias Janowitz 5,  Marcus D Goncalves 1 2
Affiliations

Affiliations

  • 1 Department of Medicine, NYU Langone Health, New York, NY.
  • 2 Department of Medicine, Weill Cornell Medicine, New York, NY.
  • 3 Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10021, USA.
  • 4 Department of Surgery, Division of Colorectal Surgery, New York-Presbyterian Weill Cornell Medical Center, New York, NY 10021, USA.
  • 5 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • 6 Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, POB 12, Rehovot 7610001, Israel.
  • 7 Weill Cornell Medical College, New York, NY 10068, USA.
  • 8 Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY 10021, USA.
  • 9 Rutgers Cancer Institute of New Jersey, Department of Molecular Biology and Biochemistry, The State University of New Jersey, New Brunswick, NJ 08901, USA, and Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA.
  • 10 Cancer Metastasis Laboratory, UCL Cancer Institute, 72 Huntley Street, London WC1E 6DD, United Kingdom.
PMID: 41278737 DOI: 10.1101/2025.10.21.683287
Abstract

Lung Cancer is the leading cause of cancer-related death and is frequently accompanied by reduced food intake and cachexia, a debilitating syndrome characterized by weight loss and skeletal muscle wasting. We sought to identify contributors to cachexia using a murine model of lung Cancer that reproduces key features of this syndrome. A multiplex cytokine screening approach, integrated with western blot and transcriptomic analyses, identified tumor-derived inflammatory mediators and downstream signaling pathways associated with cachexia. Notably, IL-6 superfamily members were elevated in the tumor and plasma of mice and patients with cachexia. The JAK-STAT3 signaling was upregulated in liver and skeletal muscle, driving the acute phase response and impairing lipid metabolism. Pharmacologic inhibition of JAK1/2 with ruxolitinib improved body weight, fat mass, and overall survival without altering tumor burden. These effects were driven primarily by blunted hypothalamic Leptin receptor signaling, which increased food intake early in the disease course. In the liver, JAK inhibition reduced STAT3 activity, restored fatty acid oxidation, and decreased the production of acute-phase proteins. These findings support JAK inhibition as a therapeutic strategy for lung cancer-associated cachexia.

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