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<p>Upper tract urothelial carcinoma (UTUC) is a rare malignancy with a significantly poorer prognosis than bladder cancer (BC). One distinguishing feature of UTUC is its enhanced resistance to reactive oxygen species (ROS)-induced lipid peroxidation, a phenomenon closely associated with adverse clinical outcomes. However, the molecular mechanisms underlying this resistance remain largely unexplored. In this study, we identify LncPEDS1-AS, an ultra-long (&gt;6900 nt) antisense lncRNA, as a key regulator of ROS resistance in UTUC. Mechanistically, LncPEDS1-AS interacts with the splicing factor DDX23, forming a nuclear RNA-protein complex that facilitates the splicing and maturation of PEDS1 pre-mRNA. PEDS1 encodes plasmanylethanolamine desaturase, which plays a protective role against lipid peroxidation. Based on these findings, we developed an antisense oligonucleotide (ASO) therapy strategy targeting LncPEDS1-AS, which effectively suppressed tumour growth and enhanced tumour cells’ ROS sensitivity both in vitro and in vivo. Moreover, our findings also highlight the distinctive molecular features and regulatory capacity of ultra-long antisense lncRNAs such as LncPEDS1-AS, which merit further comprehensive exploration in cancer biology.</p><p></p>

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LncPEDS1-AS promotes UTUC resistance to lipid peroxidation by regulating PEDS1 expression via DDX23

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Guanru Li,
  • Erwei Zhang,
  • Zhiyu Wang,
  • Zhijin Zhang,
  • Yuke Zhang,
  • Shichen Di,
  • Jingyi Lu,
  • Shun Cao,
  • Guoqing Xie,
  • Yu Zhang,
  • Keqiang Li

摘要

Upper tract urothelial carcinoma (UTUC) is a rare malignancy with a significantly poorer prognosis than bladder cancer (BC). One distinguishing feature of UTUC is its enhanced resistance to reactive oxygen species (ROS)-induced lipid peroxidation, a phenomenon closely associated with adverse clinical outcomes. However, the molecular mechanisms underlying this resistance remain largely unexplored. In this study, we identify LncPEDS1-AS, an ultra-long (>6900 nt) antisense lncRNA, as a key regulator of ROS resistance in UTUC. Mechanistically, LncPEDS1-AS interacts with the splicing factor DDX23, forming a nuclear RNA-protein complex that facilitates the splicing and maturation of PEDS1 pre-mRNA. PEDS1 encodes plasmanylethanolamine desaturase, which plays a protective role against lipid peroxidation. Based on these findings, we developed an antisense oligonucleotide (ASO) therapy strategy targeting LncPEDS1-AS, which effectively suppressed tumour growth and enhanced tumour cells’ ROS sensitivity both in vitro and in vivo. Moreover, our findings also highlight the distinctive molecular features and regulatory capacity of ultra-long antisense lncRNAs such as LncPEDS1-AS, which merit further comprehensive exploration in cancer biology.