OBJECTIVE: Skeletal muscle atrophy is a major comorbidity associated with chronic obstructive pulmonary disease caused by exposure to cigarette smoke (CS). CS-activated macrophages and pyroptosis play an important role in skeletal muscle atrophy, but its specific molecular mechanism remains unclear. This study investigated the role and mechanisms of pyroptosis and activated macrophages in CS-induced skeletal muscle atrophy. METHODS: In the in vivo model, mice were exposed to either CS or air for 24 weeks, and in the in vitro model, C2C12 murine skeletal muscle cells were co-cultured with macrophages in Transwell chambers. Western blotting, real-time PCR, ELISA, and other methods were used to detect pyroptosis-related markers to investigate the mechanism of CSE-activated macrophages on skeletal muscle atrophy and pyroptosis. RESULTS: In vivo, CS-induced atrophy of the mouse gastrocnemius muscle was accompanied by increased expression of pyroptosis-related markers, including NLRP3 inflammasome, cleaved Caspase-1, the GSDMD N-terminal domain, and interleukin (IL)-18. In vitro, CS extract (CSE)-activated macrophages mediates pyroptosis of skeletal muscle cells and induces myotube atrophy. Further studies demonstrated that macrophage-derived TNF-α is the initiating factor of skeletal muscle pyroptosis, and this process appears to be mediated through TNF-α activating the TNFR1/NLRP3/caspase-1/GSDMD signaling pathway. CONCLUSION: TNF-α released by CSE-activated macrophages can promote skeletal muscle pyroptosis by activating the TNFR1/NLRP3/Caspase-1/GSDMD signaling pathway, which likely contributes to skeletal muscle atrophy. These findings provide more insight into the mechanisms underlying skeletal muscle atrophy in COPD.