Inhibiting the NLRP3 inflammasome with MCC950 ameliorates muscle atrophy in cancer cachexia.

Cancer cachexia-associated muscle atrophy represents a critical clinical challenge in advanced malignancies. Cancer cachexia is known as an inflammation-related disease, and the NoD-like receptor family pyrin domain-3 (NLRP3) inflammasome plays a significant role in cancer cachexia, especially in muscle atrophy. In the present study, the efficacy of MCC950, a selective NLRP3 inhibitor, on cancer cachexia-associated muscle atrophy was observed both in cultured C2C12 myotubes underwent various simulated cancer cachexia injuries and in cancer cachexia model mice bearing C26 colon tumor cells. In vitro, MCC950 alleviated C2C12 myotube atrophy induced by conditioned medium from tumor or tumor-macrophage co-cultures. In vivo, MCC950 markedly attenuated cachexia symptoms such as body weight loss and muscle atrophy in C26 tumor-bearing mice. Mechanistically, in tumor or tumor-macrophage co-culture, MCC950 suppresses NLRP3 inflammasome activation, reduces IL-1β and IL-18 release, subsequently decreases the potency of inducing NF-κB activation and Atrogin-1-mediated ubiquitin-proteasome degradation in myotubes, thereby attenuates C2C12 myotube atrophy. Furthermore, in muscle cells, MCC950 directly silences NLRP3 inflammasome signaling, inhibits pyroptosis and IL-1β/IL-18 secretion, suppresses muscle protein degradation to rescue cancer cachexia-driven muscle atrophy. These findings revealed the important role of NLRP3 inflammasome in cancer cachexia and also suggested the possibility of developing NLRP3 inflammasome inhibitors such as MCC950 to be novel therapeutic candidates for cancer cachexia treatment.