Filgotinib inhibits METTL3-mediated m6A of EIF3A by targeting ERG-TBP to suppress PDAC progression JAK-STAT3-independently

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor. EIF3A has been identified as a reader of N6-methyladenosine (m⁶A) modification, influencing the translation levels of various molecules and functioning as an oncogene. Our study presents novel findings demonstrating that the m⁶A of EIF3A, regulated by METTL3, influences the stability of EIF3A mRNA and its protein expression, ultimately impacting the progression of PDAC. Notably, through high-throughput drug screening targeting m⁶A of EIF3A, we identified filgotinib-a commercially rheumatism drug, Janus kinase (JAK) -STAT3 inhibitor-as an effective inhibitor of PDAC proliferation. Filgotinib increased DNA damage in PDAC cells via the ERG-TBP-METTL3-m⁶A-EIF3A axis. In contrast, other JAK-STAT3 inhibitors such as ruxolitinib and knockdown of STAT3 does not replicate this effect, indicating that the anti-tumor effect of filgotinib is independent of JAK-STAT3 signaling. This study offers innovative insights and potential therapeutic strategies for the treatment of PDAC through EIF3A m⁶A.