Filgotinib inhibits the proliferation of pancreatic adenocarcinoma via m6A-EIF3A independent JAK-STAT3 pathway

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with poor prognosis, in which translation initiation factor EIF3A acts as an oncogene. Although EIF3A is recognized as an m?A reader, whether EIF3A itself undergoes m?A modification and its therapeutic relevance in PDAC remains unclear.

Methods: We combined bioinformatic analysis, m?A-seq, MeRIP-qPCR, and functional assays to explore the role of METTL3-dependent m?A modification of EIF3A in PDAC. High-throughput drug screening and molecular docking were performed to identify inhibitors of this axis. In vitro assays, xenograft models, and rescue experiments validated the functional effects of candidate compounds.

Results: EIF3A was overexpressed in PDAC and associated with unfavorable prognosis. m?A sequencing revealed reduced EIF3A methylation in PDAC tissues, while METTL3 knockdown decreased EIF3A mRNA stability and protein levels, thereby enhancing DNA damage. Drug screening identified Filgotinib, a JAK inhibitor, as a potent suppressor of PDAC proliferation. Mechanistically, Filgotinib targeted ERG, downregulated TBP, and subsequently inhibited the METTL3–m?A–EIF3A axis, leading to impaired DNA repair and accumulation of DNA damage. These effects occurred independently of the canonical JAK–STAT3 pathway.

Conclusion: We uncovered a novel regulatory mechanism in PDAC whereby Filgotinib inhibits tumor proliferation through the ERG–TBP–METTL3–m?A–EIF3A axis, independent of JAK–STAT3 signaling. These findings provide mechanistic insights and suggest Filgotinib as a promising therapeutic candidate for PDAC treatment.

Zhang chaolei, PhD candidate, specializes in pancreatic cancer research. His work focuses on the molecular mechanisms of tumor progression, particularly the discovery of the role of new drugs in tumorigenesis and treatment resistance. He has conducted studies that integrate bioinformatics, cell models, and in vivo experiments to investigate novel oncogenic drivers and therapeutic targets. His recent studies highlight the tumor suppressive effect of Filgotinib drug in pancreatic cancer and explore the specific mechanism by which it functions through the ERG-TBP-METTL3-m6A-EIF3A axis, aiming to provide a new approach against this deadly malignancy.