Targeting IL-6/STAT3 signaling to mitigate sarcopenia: Insights from immuno-metabolic crosstalk in NSCLC

Non-small cell lung cancer (NSCLC) is the most prevalent subtype of lung cancer and a leading cause of cancer-related mortality worldwide. Literature evidences indicates a strong association between systemic inflammation, driven by cytokines such as Interleukin-6 (IL-6), and the development of NSCLC-associated sarcopenia. However, the immuno-metabolic underpinnings that link tumor-derived IL-6 signaling to skeletal muscle degradation remain incompletely understood. We developed a comprehensive immuno-metabolic mathematical model to investigate how IL-6 signaling influences branched-chain amino acids (BCAA) metabolism and redox homeostasis in the context of NSCLC-induced sarcopenia by understanding two key causes of sarcopenia which are malnutrition and redox homeostasis. Our model proposes that IL-6 alters tumor metabolism by activating the STAT3 pathway. Elevated IL-6 impairs protein synthesis, proteolysis, and muscle atrophy by interfering with insulin signaling, inhibiting mTORC1 activation, and increasing oxidative stress. Additionally, it reveals a central role for IL-6-driven metabolic rewiring, particularly BCAA utilization and redox imbalance, in promoting NSCLC-induced sarcopenia. These findings underscore the dual impact of IL-6 on tumor progression and systemic muscle degradation, and provide a framework for evaluating therapeutic strategies that target IL-6/STAT3 signaling and amino acid metabolism via STAT3 and acetyl-CoA cross talk to mitigate NSCLC-induced sarcopenia.