An FGF21-IGFBP1 tumor-liver relay drives musculoskeletal defects in colorectal cancer cachexia

Abstract

Colorectal cancer (CRC) is frequently accompanied by cachexia, a wasting syndrome characterized by progressive loss of muscle and bone that worsens physical function and survival. Although liver dysfunction is increasingly recognized in cachexia, whether tumor-induced liver signaling contributes directly to musculoskeletal decline remains unclear. Here we show that CRC establishes a tumor-liver endocrine relay in which tumor-derived fibroblast growth factor 21 (FGF21) stimulates hepatic production of the hepatokine insulin-like growth factor binding protein 1 (IGFBP1). IGFBP1 is consistently elevated in patients with CRC and in multiple mouse models, where it promotes osteoclast differentiation, muscle atrophy, and bone loss. Genetic or pharmacological inhibition of IGFBP1 preserves muscle and bone despite persistent tumor burden, whereas deletion of tumor-derived FGF21 suppresses hepatic IGFBP1 production and mitigates musculoskeletal wasting. These findings identify a tumor-liver signaling axis that drives CRC-associated cachexia and highlight the FGF21-IGFBP1 pathway as a therapeutic target to preserve musculoskeletal health.