Curcumin, as a natural polyphenolic compound, possesses antitumor, antioxidant properties and anti-inflammatory. Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, and there is a lack of molecular mechanisms and therapeutic options regarding relevant therapeutic agents. Therefore, we investigated the mechanism of curcumin inhibiting pancreatic cancer growth by modulating proliferation of cells and cellular metabolism.Bioinformatics analysis was involved in analyzing the intersecting targets of curcumin and pancreatic ductal adenocarcinoma. The effect of curcumin on proliferation of PANC-1 cells was tested by CCK-8, and total RNA from PANC-1 was also analysed by transcriptome sequencing. Molecular docking was involved in verifying binding stability of curcumin to protein targets. Molecular dynamics simulated and evaluated binding free energy, hydrogen bonds and root mean square fluctuation of the complex.PPI, GO and KEGG were involved in screening and analysing key interacting protein targets. 40 μg/mL curcumin significantly inhibited the growth and proliferation of PANC-1. Transcriptome sequencing results showed gene expression of Cyclin D1 (CCND1), AKT serine/threonine kinase 1 (AKT1), HRas proto-oncogene (HRAS), epidermal growth factor receptor (EGFR) was significantly down-regulated by curcumin treatment. Result of molecular dynamics and molecular docking inhibited the free binding energies of CCND1/Curcumin, HRAS/Curcumin, AKT1/Curcumin and EGFR/Curcumin were -21.13 ± 3.41 kcal/mol, -21.84 ± 4.38 kcal/mol, -20.61 ± 1.82 kcal/mol and -27.37 ± 1.94 kcal/mol, respectively.We found curcumin may not only regulate cell cycle progression in PDAC and apoptosis by down-regulating HRAS, thereby inhibiting CCND1 and its downstream signaling pathways, but also inhibit energy metabolism reprogramming, Ras-RAF-MEK-ERK and other downstream signalling pathways by down-regulating EGFR and AKT1, thereby affecting tumor cell metastasis, survival and proliferation.Copyright © 2025. Published by Elsevier Inc.