Yin-Huang-Qing-Fei-Capsule derived diosgenin and its optimized nanoconjugate target STAT3 against pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is a progressive, fatal interstitial lung disease with limited curative therapeutic options. Yin-Huang-Qing-Fei (YHQF) capsule is an approved clinical Chinese patent medicine with emerging preclinical evidence of potential anti-fibrotic bioactivity, yet its core anti-PF constituents, direct functional targets, and the druggability of its key active monomer remain largely uncharacterized. PURPOSE: This study aimed to decipher the anti-PF pharmacodynamic basis of YHQF, validate its core active constituent and functional target, and optimize the druggability of the candidate monomer. STUDY DESIGN: A randomized, controlled preclinical in vivo study was conducted, coupled with in vitro pharmacological validation, transcriptomic profiling, machine learning-based constituent screening, and genetic causal inference for target prioritization. METHODS: The anti-PF efficacy of YHQF was verified in bleomycin (BLM)-induced mouse PF models. Core bioactive constituents were screened via LC-MS/MS and machine learning. Mendelian randomization (MR) was used for target prioritization, followed by molecular docking, molecular dynamics simulation, surface plasmon resonance (SPR) and siRNA assays for multi-dimensional target validation. Transcriptomic profiling was conducted to elucidate the STAT3-associated downstream regulatory pathways. A diosgenin-metformin nanoconjugate (DM) was rationally designed for druggability optimization. RESULTS: YHQF significantly alleviated BLM-induced PF in mice. Diosgenin was identified as YHQF's core anti-PF constituent, with STAT3 validated as its direct functional target. Diosgenin exerted STAT3-dependent anti-fibrotic effects, and DM nanomicelles exhibited notably enhanced in vivo anti-PF efficacy. CONCLUSION: This study defined the diosgenin-STAT3 axis as the core mechanism mediating YHQF's anti-PF effect, develops an optimized nanomedicine with improved translational potential, and provides a practical, replicable strategy for traditional Chinese medicine modernization.