Integration of Metabolomics and Transcriptomics Uncovers the Adjuvant Effects of Matrine Combined With Gemcitabine on Pancreatic Cancer Treatment

• DOI: 10.1002/orm2.70004
• Publication Date: 2025-04-01T15:48:00Z
• Authors: Chang Liu; Minjie Wang; Henan Qin; Huiying Liu; Zeming Wu; Chen Pan; Tianfu Wei; Jiwei Liu; Dong Shang; Jinpeng Yao; Peiyuan Yin

ABSTRACTBackgroundMetabolic reprogramming, an essential hallmark of pancreatic cancer (PC), affects the treatment and prognosis of patients with this malignancy. For patients with nonresectable PC, chemotherapy is the primary treatment option, with gemcitabine recognized as a first‐line chemotherapeutic drug. However, the effectiveness of gemcitabine is often compromised by the rapid development of drug resistance. This study investigated metabolic targets in PC under gemcitabine treatment and evaluated the potential of matrine, a Chinese herb extract, as an adjuvant therapy for PC.MethodsWe used metabolomics, lipidomics, and transcriptomics to investigate metabolic alterations in PC. Bioinformatics analysis was performed to identify key metabolic pathways and potential biomarkers. Various techniques, including flow cytometry, western blot analysis, immunostaining, immunohistochemistry, and TUNEL assays, were used to assess cell apoptosis and molecular changes.ResultsThe combined treatment of gemcitabine and matrine significantly enhanced cell apoptosis and inhibited invasion compared with individual treatments in Panc‐1 and H6C7 cell lines. We identified lipid metabolism as a target of matrine/gemcitabine in PC cells. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that matrine and gemcitabine modulated sphingolipid signaling pathway and cancer‐related pathways in PC. Compared with gemcitabine alone, the combination of matrine and gemcitabine resulted in significantly enhanced cell apoptosis and reduced tumor growth in a PC xenograft mouse model. Mechanistic analysis further discovered that the enhanced effect was mediated by upregulating NGFR expression and lipid metabolism.ConclusionsOur findings suggest that matrine may serve as a promising adjuvant therapy for gemcitabine in PC, functioning through modulation of lipid metabolism. This study provides a foundation for the further exploration of lipid biomarkers to improve the efficacy of chemotherapy in patients with PC.