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<p>Platinum resistance remains a major obstacle to effective treatment and improved prognosis in ovarian cancer. Although 5-methylcytosine (m<sup>5</sup>C) RNA modification has been implicated in chemoresistance, its precise functional role in ovarian cancer remains unclear. In this study, we integrated RNA-Seq and single-cell transcriptomic data from cisplatin-resistant ovarian cancer cell lines and patient samples, identifying the m<sup>5</sup>C reader protein ALYREF as a key regulator of platinum resistance. Functional studies using ALYREF and NSUN2 knockdown, overexpression, and mutant constructs—combined with multi-omics analyses (RNA-Seq, m<sup>5</sup>C-BIS-Seq, and RIP-Seq)—revealed that ALYREF binds to m<sup>5</sup>C-modified LGR4 mRNA, enhancing its stability and promoting activation of the Wnt/β-catenin signaling pathway. Critically, this regulatory mechanism is dependent on NSUN2-mediated m<sup>5</sup>C modification of LGR4 mRNA. Together, our findings demonstrate that the NSUN2/ALYREF/LGR4 axis mediates platinum resistance through m<sup>5</sup>C-dependent stabilization of LGR4 and downstream Wnt signaling activation. Thus, targeting ALYREF may represent a promising strategy to overcome platinum resistance in ovarian cancer.</p>

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Multi-omics analysis reveals that ALYREF-mediated m5C modification promotes platinum resistance in ovarian cancer via the NSUN2/ALYREF/LGR4 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • Shimin Yang,
  • Pengyuan He,
  • Wei Wang,
  • Xianming Xu,
  • Xiaowei Xi,
  • Yi Li

摘要

Platinum resistance remains a major obstacle to effective treatment and improved prognosis in ovarian cancer. Although 5-methylcytosine (m5C) RNA modification has been implicated in chemoresistance, its precise functional role in ovarian cancer remains unclear. In this study, we integrated RNA-Seq and single-cell transcriptomic data from cisplatin-resistant ovarian cancer cell lines and patient samples, identifying the m5C reader protein ALYREF as a key regulator of platinum resistance. Functional studies using ALYREF and NSUN2 knockdown, overexpression, and mutant constructs—combined with multi-omics analyses (RNA-Seq, m5C-BIS-Seq, and RIP-Seq)—revealed that ALYREF binds to m5C-modified LGR4 mRNA, enhancing its stability and promoting activation of the Wnt/β-catenin signaling pathway. Critically, this regulatory mechanism is dependent on NSUN2-mediated m5C modification of LGR4 mRNA. Together, our findings demonstrate that the NSUN2/ALYREF/LGR4 axis mediates platinum resistance through m5C-dependent stabilization of LGR4 and downstream Wnt signaling activation. Thus, targeting ALYREF may represent a promising strategy to overcome platinum resistance in ovarian cancer.