IL-6 signaling orchestrates proteolytic hubs MuRF1 and Atrogin-1 in NSCLC induced sarcopenia

Abstract

Non-small cell lung cancer (NSCLC) is frequently associated with sarcopenia, a debilitating condition of muscle wasting driven by complex tumor–muscle cross-talk. To unravel the regulatory mechanisms underlying this phenotype, we reconstructed a comprehensive signaling network integrating inflammatory, anabolic, catabolic, and proteolytic pathways. The network was translated into a mechanistic mathematical model using ordinary differential equations, enabling dynamic simulations of pathway activity. Flux analysis revealed that only a limited number of reactions dominate system behavior, with cytoplasmic IL-6 export and SMAD2/3–4 mediated induction of MuRF1 and Atrogin-1 emerging as major control points for muscle protein breakdown. Crosstalk analysis identified these proteolytic regulators as central hubs, integrating signals from inflammatory cytokines, oxidative stress, and transcriptional modulators. Principal component analysis further confirmed that sarcopenic progression is governed by a compact regulatory core, with IL-6/STAT3, myostatin/SMAD, and FOXO/NF-κB pathways converging on MuRF1 and Atrogin-1. Experimental validation using immunofluorescence-based confocal microscopy demonstrated increased expression and altered localization of these ubiquitin ligases in C2C12 cells co-cultured with lung cancer lines, corroborating model predictions. Together, these findings provide a systems-level framework that transforms broad observations of inflammation into ranked therapeutic targets and support combined strategies aimed at blocking the IL-6/STAT3–myostatin/SMAD–FOXO1/3–MuRF1/Atrogin-1 axis to mitigate NSCLC-associated sarcopenia.