Therapeutic substance basis of Bu-Ti-Hua-Tan-Tang for chronic obstructive pulmonary disease: A targeted protein extraction approach

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally, and there are some limitations in the therapeutic effect of COPD triple therapy. Bu-Ti-Hua-Tan-Tang (BTHTT), a classic Traditional Chinese Medicine formula, has demonstrated significant clinical efficacy, yet its therapeutic substance basis and mechanisms remain unclear. This study employed a targeted protein extraction strategy to broadly screen for BTHTT components that migrate into the bloodstream, focusing on core protein targets associated with key pathological targets. We achieved intelligent identification of the therapeutic substance basis and mechanisms of BTHTT. Based on the significant therapeutic effects observed in the high-dose group, we identified key metabolic small molecules such as glutathione (oxidized form), phosphatidylcholine, and L-palmitoylcarnitine, and determined critical metabolic regulatory pathways of BTHTT, including phenylalanine, tyrosine, and tryptophan biosynthesis. Furthermore, we discovered IL1β as a core protein target within its protein regulatory interaction network and elucidated the primary mechanism of BTHTT, which involves competitive reversal of the functional binding of IL1β to IL1R1 via IL1R2. We identified seven components, including tanshinone IIA and cryptotanshinone, with high binding affinity (binding energy ≤−8 kcal/mol) to the IL1R2-IL1β and IL1β-IL1R1 interactions. This study is the first to reveal the potential therapeutic substance basis of BTHTT and explore its mechanism through competitive inhibition of IL1β binding to the functional receptor IL1R1 via IL1R2. It provides a scientific basis for further investigation into the mechanisms of BTHTT and offers a novel approach for the integrated multi-omics study of Traditional Chinese Medicine formulas.