Comprehensive transcriptomic analysis identifies Lrg1 as a potential therapeutic target for preventing muscle atrophy in cancer cachexia.

Cancer cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting and systemic inflammation, primarily observed in patients with advanced-stage cancer. Cachexia severely impacts patients' quality of life and even increases mortality rates; however, effective therapeutic interventions remain elusive. To identify key mediators of muscle atrophy, we integrated >100 bulk and single-cell transcriptomic datasets from diverse murine cachexia models, including colorectal, lung, and pancreatic cancer. This analysis identified leucine-rich α-2-glycoprotein 1 (), as consistently upregulated in skeletal muscle endothelial cells across cachexia models and progressively increased during disease progression. Functional studies demonstrated that recombinant Lrg1 induced myotube atrophy in vitro, accompanied by reduced fusion index, shortened myotube length, and increased expression of the atrogenes such as MAFbx and MuRF1. Neutralization of Lrg1 or pharmacological inhibition of Stat3 prevented these effects. Our findings nominate Lrg1 as a candidate biomarker and potential therapeutic target for preventing skeletal muscle wasting in cancer cachexia. This study reports the first omics-based characterization of the CT-26 cancer cachexia model and shows transcriptomic concordance with other models. Integrative bulk and single-cell analyses identified as a gene highly expressed in endothelial cells and associated with muscle wasting. Functional assays indicated that extracellular Lrg1 activates Stat3 and induces myotube atrophy, whereas its neutralization or Stat3 inhibition prevented these effects. Lrg1 may therefore serve as a biomarker and therapeutic target in cancer cachexia.