Tongsai Granules Ameliorate Airway Mucus Hypersecretion in AECOPD by Remodeling LIPA-Driven Ceramide Metabolism

Tongsai Granules (TSG) is a traditional Chinese medicine formula traditionally used for the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with phlegm-heat obstructing lung syndrome, a condition characterized by cough, excessive sputum production, and dyspnea; however, its underlying therapeutic mechanisms remain unclear.

To investigate the mechanisms by which TSG alleviates airway mucus hypersecretion in AECOPD through regulation of the LIPA/ceramide axis.

A murine AECOPD model and airway epithelial cells were used. Proteomic and lipidomic analyses, molecular docking, surface plasmon resonance (SPR), drug affinity responsive target stability (DARTS), and LIPA overexpression and knockdown assays were performed.

TSG improved pulmonary function, attenuated lung injury and inflammation, and suppressed MUC5AC expression in AECOPD mice. Multi-omics analyses showed that TSG regulated lipid metabolism and reduced triglyceride and ceramide accumulation while downregulating lysosomal acid lipase A (LIPA). Several serum-exposed constituents of TSG inhibited MUC5AC expression. Bergenin (BER) was selected as a representative bioactive constituent for subsequent target-identification and mechanistic studies. Molecular docking, SPR, and DARTS assays demonstrated direct interaction between BER and LIPA. LIPA knockdown suppressed MUC5AC expression, whereas LIPA overexpression attenuated the inhibitory effect of BER. Moreover, exogenous ceramide reversed BER-mediated suppression of MUC5AC.

TSG alleviates airway mucus hypersecretion in AECOPD by targeting the LIPA/ceramide axis. Bergenin directly targets LIPA to regulate lipid metabolism and suppress MUC5AC overexpression.