Abstract

Ferulic acid (FA) was reported for its chemoprotective anticancer properties in various cancers, including lung and breast cancers. However, the exact molecular mechanism of FA targeting the JAK-STAT pathway in gastrointestinal (GI) cancers such as colon and gastric cancers, has yet to be explored. Hence, our study aims to decipher the molecular mechanism of FA by targeting the JAK-STAT pathway in GI cancers through an integrated approach of network pharmacology and molecular simulation, which would provide a new targeted therapy for GI cancers. Subsequently, various in vitro experimental validation assays, including cell proliferation assay, AO/EtBr, DAPI staining, gene and protein expression analysis, were performed on SW620 and AGS cell lines to check for the anticancer potential of FA. A total of 92 potential FA targets for GI cancer treatment were identified. Moreover, 370 entries and 72 pathways were discovered through GO and KEGG analysis. Network pharmacology data indicated that FA targets STAT3 via the JAK-STAT pathway. The molecular docking and simulations showed a high binding affinity between FA and STAT3 (-6.7 kcal/mol). Also, FA exhibited strong cytotoxic effects on GI cancer cell lines (SW620- IC50 302 µg/ ml and AGS-IC50 205 µg/ml), apoptosis validated by apoptotic staining. Further, the gene and protein expression analysis revealed the downregulation of JAK2 and STAT3 of the JAK/STAT pathway. Thus, our approach with network pharmacology and in vitro experiments has suggested that FA could be a promising drug against GI cancers.

Key words: Colon cancer, Ferulic acid, Gastric cancer, JAK-STAT pathway, Molecular docking, Network pharmacology