Wheat Bran Stir-Frying Reshapes the Metabolome of Euryale Ferox Seeds and Predicts Enhanced Bioactive Potential for Spleen and Kidney Tonifying

Background: Euryale ferox Salisb. seed (Euryales Semen) is a traditional Chinese medicine whose therapeutic application is modulated by wheat bran stir-frying, a process that enhances its effects on tonifying the spleen and kidney. The molecular mechanisms and alterations in bioactive components underlying this processing-enhanced efficacy remain to be fully elucidated. This study aimed to systematically investigate the impact of wheat bran stir-frying on the metabolite profile of Euryales Semen and to reveal its potential pharmacological mechanisms. Methods: An integrated strategy combining UPLC-MS/MS-based metabolomics, network pharmacology, and molecular docking was employed. First, differential metabolites between raw and processed Euryales Semen were identified and quantified. Second, a “metabolite-target-disease” network was constructed to predict core targets and pathways. The docking protocol was validated by re-docking of co-crystallized ligands, with all RMSD values below 2.0 Å. Finally, molecular docking was used to predict the binding interactions between key metabolites and potential protein targets. Results: A total of 1597 metabolites were identified, and 244 were defined as differentially expressed (VIP > 1, |log2(FC)| ≥ 1). Processing significantly upregulated 19 of the 22 key metabolites identified, with Urolithin B showing the most dramatic increase (168-fold), which was identified with Level 1 confidence using an authentic standard. Network pharmacology analysis identified 10 core targets (e.g., MMP2, MMP9, AKR1B1) primarily associated with tumors, diabetes, and other chronic diseases. Molecular docking predicted strong binding affinities (<−9.0 kcal·mol−1) between these core targets and key upregulated metabolites, including Urolithin B, Tangeretin, and Syringetin. Conclusions: This study suggests that wheat bran stir-frying fundamentally reshapes the metabolic profile of Euryales Semen, leading to the enrichment of bioactive metabolites (e.g., Urolithin B) and suggesting a potential for enhanced tonifying, anti-tumor, and anti-diabetic activities that warrants further experimental investigation. The dramatic increase in the content of Urolithin B, a metabolite not commonly found in plants, raises the hypothesis of a processing-induced chemical transformation, which warrants further experimental validation, and highlights its potential as a critical component for the herb’s efficacy. The findings offer a preliminary computational basis for understanding traditional processing practices, linking traditional knowledge with modern scientific evidence.