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<p>Pancreatic ductal adenocarcinoma is among the most lethal malignancies, underscoring the urgent need for a deepened molecular insights and targeted strategies. While microRNAs (miRNAs) are known to regulate key oncogenic pathways in PDAC, most studies overlook the functional heterogeneity between the 3p and 5p strands derived from the same miRNA precursor. Here, we systematically investigate the strand-specific roles of miR-301a-3p and miR-301a-5p in PDAC progression. Using a multidimensional approach, including clinical tissue-based FISH, serum analysis, cell-based assays, and xenograft models, we revealed a consistent pattern of miR-301a-3p upregulation and miR-301a-5p downregulation in PDAC tissues and fluids. Importantly, the ratio of 5p to 3p is negatively correlated with TNM stage, and its combination with CA19-9 significantly improves prognostic prediction. Mechanically, the two strands exert opposing effects on tumor progression via distinct cell death pathways. miR-301a-3p promotes tumorigenesis by targeting ACSL4 to suppress ferroptosis, while miR-301a-5p induces pyroptosis by activating NF-κB pathway through CEACAM6-TNFR1 axis. These findings challenge the prevailing “dominant strand” paradigm and uncover a previously unrecognized antagonism between miRNA strands. By highlighting the risks of indiscriminate miRNA targeting, our work supports the development of strand-specific diagnostic and therapeutic strategies in PDAC. This study advances the concept of chain-level regulation as a foundation for precision oncology.</p> Graphical Abstract <p></p> <p>Graphical Headlights<UnorderedList Mark="None"> <ItemContent> <p>Paradigm Shift: We challenge the conventional miRNA therapy by revealing the functional antagonism between miR-301a-3p (oncogenic) and miR-301a-5p (tumor-suppressive).</p> </ItemContent> <ItemContent> <p>Novel Mechanism: A single precursor fine-tunes PDAC fate via two strands differentially regulating ferroptosis (via ACSL4) and pyroptosis (via NF-κB).</p> </ItemContent> <ItemContent> <p>Clinical Translation: Our findings enable chain-specific diagnostics and therapeutics, overcoming the limitations of traditional miRNA targeting.</p> </ItemContent> </UnorderedList></p>

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Strand-specific functions of miR-301a-3p and -5p drive opposing roles in pancreatic cancer via ferroptosis and pyroptosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月28日

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  • Yuhang Chen,
  • Suoyi Dai,
  • Wenxun Cai,
  • Jiangang Zhao,
  • Fenglin Zhang,
  • Chien-Shan Cheng,
  • Lianyu Chen

摘要

Pancreatic ductal adenocarcinoma is among the most lethal malignancies, underscoring the urgent need for a deepened molecular insights and targeted strategies. While microRNAs (miRNAs) are known to regulate key oncogenic pathways in PDAC, most studies overlook the functional heterogeneity between the 3p and 5p strands derived from the same miRNA precursor. Here, we systematically investigate the strand-specific roles of miR-301a-3p and miR-301a-5p in PDAC progression. Using a multidimensional approach, including clinical tissue-based FISH, serum analysis, cell-based assays, and xenograft models, we revealed a consistent pattern of miR-301a-3p upregulation and miR-301a-5p downregulation in PDAC tissues and fluids. Importantly, the ratio of 5p to 3p is negatively correlated with TNM stage, and its combination with CA19-9 significantly improves prognostic prediction. Mechanically, the two strands exert opposing effects on tumor progression via distinct cell death pathways. miR-301a-3p promotes tumorigenesis by targeting ACSL4 to suppress ferroptosis, while miR-301a-5p induces pyroptosis by activating NF-κB pathway through CEACAM6-TNFR1 axis. These findings challenge the prevailing “dominant strand” paradigm and uncover a previously unrecognized antagonism between miRNA strands. By highlighting the risks of indiscriminate miRNA targeting, our work supports the development of strand-specific diagnostic and therapeutic strategies in PDAC. This study advances the concept of chain-level regulation as a foundation for precision oncology.

Graphical Abstract

Graphical Headlights

Paradigm Shift: We challenge the conventional miRNA therapy by revealing the functional antagonism between miR-301a-3p (oncogenic) and miR-301a-5p (tumor-suppressive).

Novel Mechanism: A single precursor fine-tunes PDAC fate via two strands differentially regulating ferroptosis (via ACSL4) and pyroptosis (via NF-κB).

Clinical Translation: Our findings enable chain-specific diagnostics and therapeutics, overcoming the limitations of traditional miRNA targeting.