Targeting Muscle-Specific E3 Ligases in Cancer Cachexia Through Structure-Based Virtual Screening of Small-Molecule Inhibitors.

Cachexia is a multifactorial metabolic syndrome characterized by severe skeletal muscle loss that cannot be reversed by nutritional support. Common in cancer and other chronic diseases, it significantly increases morbidity and mortality. Muscle wasting is primarily driven by activation of the ubiquitin-proteasome pathway through the E3 ubiquitin ligases MuRF1 and Atrogin-1, which promote protein degradation and muscle atrophy. This study used computational modeling and docking to identify small-molecule inhibitors targeting these ligases, including repurposed drugs with anti-cachectic potential. Thalidomide and EM12-So2F were prioritized based on integrated docking, binding affinity, and drug-likeness/ADME analyses for validation in C2C12 myotube-based cachexia models.