Objective To develop an integrated strategy for rapid screening of pancreatic lipase (PPL) inhibitors from Rheum palmatum and systematically investigate their potential anti-obesity mechanisms. Methods Fe₃O₄@SiO₂@PPL was synthesized via chemical co-precipitation, Stöber method, and cross-linking, and characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The Fe₃O₄@SiO₂@PPL was applied in ligand fishing experiments on an ethanol extract of R. palmatum, and the captured ligands were identified by UPLC with reference standards. Molecular docking and network pharmacology were integrated to conduct mechanism prediction from multiple dimensions such as molecular interaction, target mapping, and pathway enrichment. Results Material characterization revealed the presence of an enzyme coating layer on the surface, along with characteristic absorption peaks of Fe-O, Si-O-Si, and -NH₂, indicating that pancreatic lipase was successfully immobilized on the carrier surface. Four compounds were specifically captured by fishing experiments, including chrysophanol-8-O-β-D-glucopyranoside, aloe-emodin, rhein, and chrysophanol. Among them, chrysophanol and aloe-emodin exhibited high inhibitory effects against pancreatic lipase, with median inhibition concentration (IC₅₀) values of 67.03 and 85.86 μmol/L, respectively. Molecular docking suggested that the active components can form hydrogen bonds and hydrophobic interactions with key amino acid residues of pancreatic lipase. Network pharmacology identified 150 overlapping targets between the active components and obesity. Screening out the five core targets: epidermal growth factor receptor (EGFR) and protein kinase B1 (AKT1), proto-oncogene tyrosine-protein kinase Src (SRC), heat shock protein 90 alpha family class A member 1 (HSP90AA1), and B-cell lymphoma-2 (BCL2). Pathway enrichment analysis indicated that the HIF-1 signaling pathway and the lipid and atherosclerosis pathway were the main mechanisms of action. Conclusion An integrated approach combining material-based screening, computational validation, and network prediction was established. This strategy provides an efficient tool for high-throughput screening of bioactive compounds from traditional Chinese medicines and offers methodological insights into clarifying the multi-target action mechanism of traditional Chinese medicine from the perspective of systems biology.

anti-obesity  /  pancreatic lipase inhibitor  /  Rheum palmatum L.  /  enzyme immobilization  /  ligand fishing  /  network pharmacology  /  molecular docking  /  chrysophanol-8-O-β-D-glucopyranoside  /  aloe-emodi  /  rhein  /  chrysophanol