Scutellarein attenuates cancer cachexia-induced muscle atrophy via targeted inhibition of the JAK/STAT pathway

Cancer cachexia is a multifaceted metabolic syndrome characterized by severe loss of skeletal muscle and adipose tissue, diminishing both quality of life and survival in cancer patients. Despite its prevalence, effective treatments for cancer cachexia remain limited. The JAK/STAT signaling pathway has been identified as a key driver of muscle atrophy in cachexia. This study aimed to investigate the therapeutic potential of scutellarein, a natural compound, as a JAK kinase inhibitor to prevent and mitigate cancer cachexia-induced muscle atrophy. In vitro experiments were conducted using the mouse myoblast cell line C2C12 and human induced pluripotent stem cell (hiPSC)-derived skeletal muscle cells. Myotube atrophy was induced using IFN-γ/TNF-α and cancer cell-conditioned media. Two independent mouse models of cancer cachexia were utilized for in vivo analysis. Muscle tissues were examined through transcriptomic and molecular analyses, including RNA sequencing, PCR, and immunoblotting. Structure-activity relationship studies and molecular docking analyses were performed to investigate the binding interaction of scutellarein with JAK kinases. Through a chemical library screen, we identified scutellarein as a potent JAK kinase inhibitor. Scutellarein effectively mitigated myotube atrophy by inhibiting protein degradation and promoting protein synthesis in C2C12 and hiPSC-derived muscle cells. In two distinct mouse models of cancer cachexia, scutellarein treatment significantly reduced muscle wasting, improved muscle strength and function, and countered fat depletion. Transcriptomic and molecular analyses of muscle tissues further demonstrated that scutellarein inhibited activation of JAK/STAT pathways and restored suppression of myogenesis and mitochondrial biogenesis. Structure-activity relationship analyses further revealed critical hydroxyl group positions essential for JAK binding. Collectively, our findings suggest scutellarein as a promising candidate for the prevention and treatment of cancer cachexia, providing a novel therapeutic approach to address this critical unmet need in cancer care.