Abstract
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.
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The original contributions presented in the study are included in the article/supplementary material and further inquiries can be directed to the corresponding author.
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This study did not involve the development of any custom code. All analyses were performed using standard, publicly available software tools, as described in the Methods section.
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Acknowledgements
This study was financially supported by the Natural Science Foundation of China No. 82373162; Zhejiang Provincial Natural Science Foundation of China under Grant No. LTGD23H160007.
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Chaolei Zhang: Conceptualization, Validation, Investigation, Writing - Original Draft, Project administration. Jianghao Ren: Validation, Resources. Kexiong Qiao: Validation, Resources. Chengjie Xu: Software. Xiaofan Pu: Resources. Zongrong Chen: Visualization. Liangjing Zhou: Visualization. Liping Cao: Conceptualization, Writing - Review & Editing, Funding acquisition. Shengnan Jia: Conceptualization, Writing - Review & Editing, Project administration, Funding acquisition. All authors read and approved the final manuscript.
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Zhang, C., Ren, J., Qiao, K. et al. Filgotinib inhibits METTL3-mediated m6A of EIF3A by targeting ERG-TBP to suppress PDAC progression JAK-STAT3-independently. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01396-z
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DOI: https://doi.org/10.1038/s41698-026-01396-z
