Year: 2026
Type: preprint
Abstract: Cancer cachexia is a debilitating wasting syndrome associated with involuntary weight loss, reduced appetite and food intake, adipose and muscle atrophy, and systemic inflammation with induction of a myriad of candidate cachexia factors. Using a multi-omic approach in a genetically engineered mouse model of lung cancer cachexia, we found that early circulating metabolic alterations preceded overt weight loss. Although both cachexia and fasting are characterized by a reduction in food intake, we show that the systemic metabolic changes in cachexia are distinct, indicating a lack of induction in the normal protective response to negative energy balance during cachexia. Cancer cachexia causes profound hepatic reprogramming, and activation of inflammatory programs, alongside muscle atrophy and elevation of circulating cytokines. However, targeting individual candidate cachectic factors such as IL-6, TNF-α, GDF15, CCL2, LIF, and IL17A failed to rescue weight loss or prolong survival. In contrast, caloric restriction initiated prior to tumor induction elicited a program of protection during tumor progression that attenuated multi-tissue inflammatory and catabolic transcriptional responses, preserved lean mass, and prolonged survival. Together, these findings suggest that metabolic preconditioning broadly dampens systemic inflammation and delays the onset and progression of cancer cachexia. HIGHLIGHTS: Despite both fasting and cachexia involve reduced nutrient intake, the metabolic alterations are distinct.Cachexia induces a systemic inflammatory response.Single targeting of implicated cachectic factors fails to rescue weight loss or survival in cancer cachexia.Caloric restriction pre-conditioning to enforce the protective response to nutrient limitation attenuates cachexia.
Authors: Maria Gomez-Jenkins, Trishna Das, Maria Ibrahim, Damon Fard, Sereno Lopez-Darwin, Justine Raeber, Jesse Powers, Zhixian Hu, Hirak Sarkar, Eduardo CararoLopes, Akshada Sawant, Gabriela Reyes-Castellanos, Wenyun Lu, Hantao Qiang, Aslihan Sen, Young-Yon Kwon, Selina Wadhera, Honiyah Armughan, Shang Shi, Joshua D. Rabinowitz, Sheng Hui, Tracy G. Anthony, Michael A. Skinnider, Benjamin J Raphael, Marcus D. Goncalves, Tobias Janowitz, Eileen White
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221114280