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<p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor. EIF3A has been identified as a reader of N6-methyladenosine (m<sup>6</sup>A) modification, influencing the translation levels of various molecules and functioning as an oncogene. Our study presents novel findings demonstrating that the m<sup>6</sup>A 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 m<sup>6</sup>A 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-m<sup>6</sup>A-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 m<sup>6</sup>A.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Chaolei Zhang,
  • Jianghao Ren,
  • Kexiong Qiao,
  • Chengjie Xu,
  • Xiaofan Pu,
  • Zongrong Chen,
  • Liangjing Zhou,
  • Liping Cao,
  • Shengnan Jia

摘要

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.