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Background <p>Ovarian cancer (OC) has a dismal prognosis due to late diagnosis and platinum resistance, with the molecular mechanisms linking cuproptosis, lncRNAs, and the tumor microenvironment (TME) remaining poorly defined. LncRNA ENSG00000253374 was previously identified as a prognostic biomarker for OC, while its correlation with cuproptosis and platinum resistance remains unclear.</p> Methods <p>Integrated bulk RNA-seq (TCGA-OV) and single-cell RNA-seq (GSE300897) analyses were performed, combined with in vitro CCK-8 assays, intracellular Cu⁺ detection, survival analysis, WGCNA, pseudotime trajectory, CellChat, virtual knockout, and functional enrichment analyses. OC cells with ENSG00000253374 knockdown were subjected to cuproptosis induction, and GLS-centered co-expression patterns and TME features were characterized.</p> Results <p>ENSG00000253374 knockdown correlates with altered cellular response to cuproptosis induction, and shows close expression correlation with GLS. The ENSG00000253374–GLS correlated signature is linked to abnormal glutamine metabolism, cell cycle and stemness features, and is associated with immunosuppressive myeloid differentiation and enhanced pro-resistance intercellular communication that correlate with platinum refractoriness. WGCNA constructed a GLS-centered co-expression network enriched in immune and stromal remodeling pathways; in silico GLS perturbation predicted altered stemness, angiogenesis and apoptotic signaling signatures. Elevated GLS expression in tumor and stromal cells coincides with stronger TME crosstalk and dominant M2 macrophage populations.</p> Conclusion <p>LncRNA transcripts of the ENSG00000253374 locus are associated with platinum-resistant ovarian cancer phenotypes via a GLS-related correlative signature, alongside disrupted cuproptosis and metabolic-immune remodeling. Our in vitro assays reflect overall transcriptional activity of this genomic locus rather than single splice variant function. ENSG00000253374 and GLS may serve as candidate prognostic biomarkers. Combinatorial interventions targeting this correlative axis together with cuproptosis inducers or immune modulators could provide potential strategies to relieve platinum resistance in OC.</p>

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Multi-omics profiling reveals LncRNA ENSG00000253374 as a regulator of GLS-mediated cuproptosis and platinum resistance in ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Rujun Chen,
  • Qiran Sun,
  • Jina Chen,
  • Yating Huang,
  • Ying Yang,
  • Ningning Hu,
  • Susu Jiang,
  • Xiaoqin Wang,
  • Liwen Zhang,
  • Ke Sun,
  • Fuyun Dong

摘要

Background

Ovarian cancer (OC) has a dismal prognosis due to late diagnosis and platinum resistance, with the molecular mechanisms linking cuproptosis, lncRNAs, and the tumor microenvironment (TME) remaining poorly defined. LncRNA ENSG00000253374 was previously identified as a prognostic biomarker for OC, while its correlation with cuproptosis and platinum resistance remains unclear.

Methods

Integrated bulk RNA-seq (TCGA-OV) and single-cell RNA-seq (GSE300897) analyses were performed, combined with in vitro CCK-8 assays, intracellular Cu⁺ detection, survival analysis, WGCNA, pseudotime trajectory, CellChat, virtual knockout, and functional enrichment analyses. OC cells with ENSG00000253374 knockdown were subjected to cuproptosis induction, and GLS-centered co-expression patterns and TME features were characterized.

Results

ENSG00000253374 knockdown correlates with altered cellular response to cuproptosis induction, and shows close expression correlation with GLS. The ENSG00000253374–GLS correlated signature is linked to abnormal glutamine metabolism, cell cycle and stemness features, and is associated with immunosuppressive myeloid differentiation and enhanced pro-resistance intercellular communication that correlate with platinum refractoriness. WGCNA constructed a GLS-centered co-expression network enriched in immune and stromal remodeling pathways; in silico GLS perturbation predicted altered stemness, angiogenesis and apoptotic signaling signatures. Elevated GLS expression in tumor and stromal cells coincides with stronger TME crosstalk and dominant M2 macrophage populations.

Conclusion

LncRNA transcripts of the ENSG00000253374 locus are associated with platinum-resistant ovarian cancer phenotypes via a GLS-related correlative signature, alongside disrupted cuproptosis and metabolic-immune remodeling. Our in vitro assays reflect overall transcriptional activity of this genomic locus rather than single splice variant function. ENSG00000253374 and GLS may serve as candidate prognostic biomarkers. Combinatorial interventions targeting this correlative axis together with cuproptosis inducers or immune modulators could provide potential strategies to relieve platinum resistance in OC.