HMGB1-mediated pyroptosis promotes inflammation and contributes to skeletal muscle atrophy induced by cigarette smoke.

Skeletal muscle atrophy and dysfunction are common comorbidities in chronic obstructive pulmonary disease (COPD), with cigarette smoke (CS) exposure being a significant contributing factor. However, the underlying mechanisms remain unclear. Inflammation driven by damage-associated molecular patterns (DAMPs), such as High-mobility group box 1 (HMGB1), may play a crucial role. This study investigated the involvement of HMGB1-mediated pyroptosis associated with skeletal muscle atrophy in COPD. Serum HMGB1 levels were measured in healthy nonsmokers and patients with COPD. Additionally, midthigh circumference and body mass index (BMI) were assessed in patients with COPD, and their correlations with HMGB1 levels were analyzed. Treatment with glycyrrhizin (GL, a direct inhibitor of HMGB1) in CS-exposed mice was further used to demonstrate the effect of HMGB1 on skeletal muscle. A C2C12 cell model exposed to cigarette smoke extract (CSE) was employed to elucidate the role of the HMGB1/Toll-like receptor 4 (TLR4)-NLR family pyrin domain-containing 3 (NLRP3)-gasdermin D (GSDMD)-Caspase-1 pathway. In patients with COPD, serum HMGB1 levels were significantly higher than in healthy individuals and negatively correlated with midthigh circumference and BMI. Treatment with GL in CS-exposed mice led to the reversal of muscle atrophy and dysfunction, alongside a reduction in the expression of TLR4 and pyroptosis-associated factors within skeletal muscle. In vitro experiments demonstrated that CSE increased HMGB1, which promoted skeletal muscle atrophy by driving inflammation through the HMGB1/TLR4-NLRP3-GSDMD-Caspase-1 pathway. HMGB1 induced by CS may trigger skeletal muscle atrophy. It promotes inflammation through HMGB1/TLR4-NLRP3-GSDMD-Caspase-1-mediated pyroptosis, thereby exacerbating muscle wasting. Therefore, the pathway represents a potential novel therapeutic target for skeletal muscle atrophy. This study reveals that the levels of High-mobility group box 1 (HMGB1) protein in patients with chronic obstructive pulmonary disease (COPD) are significantly higher than in healthy nonsmoking individuals and are negatively correlated with the degree of skeletal muscle atrophy. Through in vivo and in vitro experiments, we have confirmed that HMGB1 promotes inflammatory responses through the HMGB1/TLR4-NLRP3-GSDMD-Caspase-1-mediated pyroptosis pathway, thereby exacerbating muscle wasting. This pathway represents a potential novel therapeutic target for the treatment of skeletal muscle atrophy.