传统的甘草牛奶加工对中华铝（Lour.）有害，通过EGFR/PI3K/AKT通路调节降低肝毒性并增强生物活性

【ETHNOPHARMACOLOGICAL RELEVANCE】Alangium chinense (Lour.) Harms (AC) is a traditional Miao medicinal plant widely used to treat rheumatic and inflammatory disorders. Despite its therapeutic benefits, AC exhibits hepatotoxicity, limiting its safe clinical application. Traditional processing with licorice and milk has been historically employed to reduce toxicity and enhance efficacy, yet its chemical basis and underlying mechanisms remain incompletely understood.

【AIM OF THE STUDY】This study aimed to elucidate how licorice-milk processing alters the chemical composition of AC, identify key blood-absorbed constituents, and clarify the mechanisms underlying detoxification and efficacy enhancement.

【MATERIALS AND METHODS】AC was processed using an optimized licorice-milk decoction via a multi-index orthogonal design. Toxicological and pharmacological effects of raw (RAC) and processed AC (PAC) were evaluated in rats through serum biochemistry, histopathology, and xylene-induced ear edema assays. UPLC-MS/MS-based metabolomics and serum pharmacochemistry identified chemical and blood-absorbed constituents. Network pharmacology, molecular docking, and Western blotting were employed to analyze hepatotoxicity-related targets and validate the involvement of signaling pathways.

【RESULTS】Processing significantly altered the chemical profile of AC, reducing total toxic alkaloids by 27.1% while increasing flavonoids and phenols by 14.8% and 50.2%, respectively. PAC significantly decreased rat serum AST, ALT, and ALP levels, mitigated hepatic tissue injury, and inhibited xylene-induced ear edema. Metabolomic analysis identified 56 differential compounds, with 16 unique to PAC. Serum pharmacochemistry revealed 175 blood-absorbed components, 27 of which were differentially associated with hepatotoxicity, including 18β-glycyrrhetinic acid, enoxolone, and anabasine. Network pharmacology highlighted the EGFR/PI3K/AKT cascade as a core network. Molecular docking and 100-ns MD simulations demonstrated that representative compounds formed thermodynamically stable complexes within the active site of the downstream kinase AKT1 (backbone RMSD ≈ 0.238 - 0.246 nm). Tissue-level Western blotting demonstrated that PAC modulated the aberrant expression of EGFR, p-PI3K/PI3K, and p-AKT/AKT induced by RAC, suggesting the potential involvement of this axis in mitigating hepatotoxicity.

【CONCLUSION】Licorice-milk processing of AC mitigates hepatotoxicity while preserving anti-inflammatory efficacy by modulating toxic alkaloids and protective metabolites. The attenuation of liver toxicity is closely associated with the systemic regulation of the EGFR/PI3K/AKT signaling pathway. These findings provide dynamic biophysical insights into traditional processing and support the safe clinical application of AC.