Abstract 801: Mechanism of oxaliplatin-induced cachexia: A transcriptional and physiological perspective

Abstract Background: Cancer cachexia is a multifactorial, largely irreversible metabolic disorder characterized by skeletal muscle and adipose tissue depletion that is responsible for 20% of cancer-related deaths. Oxaliplatin, a chemotherapeutic agent commonly used to treat colorectal cancer and other malignancies, is associated with weight loss, muscle weaknesses, and metabolic dysregulation. Yet it is unknown whether oxaliplatin mediates these effects independently of cancer. Methods: Non-tumor-bearing immunocompetent C57BL/6 mice were administered a human-equivalent dose of oxaliplatin over 8 weeks. Metabolic parameters were assessed using metabolic cages and EchoMRI, followed by post-mortem bulk RNA sequencing of muscle, adipose tissue, and the hypothalamus. The results were compared to data sets from cachexia models in cancer and fasting. Results: Oxaliplatin induced significant weight loss (∼12%), decreased lean mass, reduced food intake, decreased physical activity, and lowered core body temperature. Adipose tissue exhibited extensive transcriptional dysregulation, with over 2,000 differentially expressed genes (DEGs) affecting metabolic and inflammatory pathways. Muscles exhibited transcriptional evidence of atrophy, supported by histological images. Hypothalamic RNA-seq revealed dysregulated thermogenic and adipocytokine pathways and overexpression of neuropeptides such as neuropeptide Y (NPY), linking peripheral metabolic changes to central regulation. Comparisons with clinical and preclinical cancer and fasting models demonstrated overlapping yet distinct transcriptional signatures. Conclusion: Our study demonstrates that oxaliplatin independently induces cachexia-like symptoms via transcriptional and metabolic disruptions peripherally in muscle, adipose tissue, and centrally in the hypothalamus. The findings point to the importance of identifying early cachexia diagnostic markers and targeted interventions to stop and reverse cachexia during oxaliplatin treatment. Significance: Adipokines such as leptin and GDF15 may be potential biomarkers of oxaliplatin-induced cachexia, and the associated metabolic pathways could be targeted therapeutically to improve cancer patient outcomes. Citation Format: Junwei Du, Rachel L. Mintz, Rachael Field, Leland C. Sudlow, John E. Morley, Jonathan R. Brestoff, Gwendalyn J. Randolph, Mikhail Y. Berezin. Mechanism of oxaliplatin-induced cachexia: A transcriptional and physiological perspective [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 801.