Tumor-derived MG53 aggravates gastrointestinal cancer cachexia related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway.

BACKGROUND: Cancer cachexia is a multisystem syndrome characterized by progressive skeletal muscle atrophy, anorexia, and weight loss, imposing a substantial global health burden. Gastrointestinal cancer cachexia is highly prevalent, yet its pathogenesis remains poorly understood, and there is currently a lack of effective diagnostic methods and therapeutic strategies specifically targeting muscle atrophy. Identifying diagnostic and therapeutic targets for gastrointestinal cancer cachexia-related muscle atrophy represents a critical challenge. METHODS: This study investigated the role of MG53 in gastrointestinal cancer cachexia. Serum MG53 levels were analyzed in patients, and experimental models examined tumor-derived MG53 effects on cancer cachexia-related muscle atrophy. RESULTS: Elevated serum MG53 levels were found in gastrointestinal cancer cachexia patients. Tumor-derived MG53 aggravates cancer cachexia-related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway in muscle. CONCLUSIONS: MG53 is identified as a novel cancer cachexia factor driving gastrointestinal cancer cachexia-related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway in muscle. MG53 correlates with muscle atrophy, supporting its potential as a diagnostic biomarker and therapeutic target of gastrointestinal cancer cachexia.