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<p>Glioma progression is heavily driven by heterogeneity and a highly immunosuppressive tumor microenvironment (TME). This study aimed to identify a robust long non-coding RNA (lncRNA) prognostic signature and elucidate its role in TME remodeling. An unbiased transcriptome-wide screening of the TCGA and CGGA databases was performed. A prognostic risk signature was constructed using univariate and multivariate Cox regression. Based on multivariate coefficients, the core protective gene SNAI3-AS1 was selected for in vitro validation in U87 and U251 cells. Additionally, a U87-derived conditioned medium (CM) co-culture system was established to investigate the cooperative reinforcement of SNAI3-AS1 overexpression and the ferroptosis inducer erastin on macrophage polarization (THP-1 cell line), assessed via RT-qPCR and ELISA. A 23-lncRNA prognostic signature was established, demonstrating high accuracy in predicting overall survival and correlating positively with immunosuppressive M2 macrophage infiltration. RT-qPCR results revealed that SNAI3-AS1 was significantly downregulated in glioma tissues. While SNAI3-AS1 overexpression did not alter cell proliferation, it profoundly suppressed three-dimensional matrix migration and invasion. Moreover, SNAI3-AS1 overexpression cooperates with erastin to elevate cellular levels of malondialdehyde and Fe<sup>2+</sup>, thereby promoting ferroptosis. Crucially, the CM co-culture model revealed that SNAI3-AS1 overexpression cooperated with erastin to trigger robust microenvironmental remodeling, repolarizing macrophages toward an antitumor M1 phenotype. This was evidenced by significantly upregulated M1 markers (iNOS, IL-6, TNF-α) and suppressed M2 markers expression (CD206, IL-10). Administration of ferrostatin-1 completely abrogated these polarization shifts, confirming a ferroptosis-dependent mechanism. We established a robust transcriptome-wide prognostic tool and identified SNAI3-AS1 as a specific suppressor of glioma invasion. Furthermore, SNAI3-AS1 cooperates with ferroptosis induction to drive M1 macrophage polarization, offering a promising TME-remodeling therapeutic strategy.</p>

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Identification of a lncRNA prognostic signature reveals that SNAI3-AS1 cooperates with erastin to reshape macrophage polarization in glioma

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Xiaochen Niu,
  • Aijie Guo,
  • Yifan Wang,
  • Hao Li,
  • Hongming Ji,
  • Rui Cheng,
  • Xiangyu Wei

摘要

Glioma progression is heavily driven by heterogeneity and a highly immunosuppressive tumor microenvironment (TME). This study aimed to identify a robust long non-coding RNA (lncRNA) prognostic signature and elucidate its role in TME remodeling. An unbiased transcriptome-wide screening of the TCGA and CGGA databases was performed. A prognostic risk signature was constructed using univariate and multivariate Cox regression. Based on multivariate coefficients, the core protective gene SNAI3-AS1 was selected for in vitro validation in U87 and U251 cells. Additionally, a U87-derived conditioned medium (CM) co-culture system was established to investigate the cooperative reinforcement of SNAI3-AS1 overexpression and the ferroptosis inducer erastin on macrophage polarization (THP-1 cell line), assessed via RT-qPCR and ELISA. A 23-lncRNA prognostic signature was established, demonstrating high accuracy in predicting overall survival and correlating positively with immunosuppressive M2 macrophage infiltration. RT-qPCR results revealed that SNAI3-AS1 was significantly downregulated in glioma tissues. While SNAI3-AS1 overexpression did not alter cell proliferation, it profoundly suppressed three-dimensional matrix migration and invasion. Moreover, SNAI3-AS1 overexpression cooperates with erastin to elevate cellular levels of malondialdehyde and Fe2+, thereby promoting ferroptosis. Crucially, the CM co-culture model revealed that SNAI3-AS1 overexpression cooperated with erastin to trigger robust microenvironmental remodeling, repolarizing macrophages toward an antitumor M1 phenotype. This was evidenced by significantly upregulated M1 markers (iNOS, IL-6, TNF-α) and suppressed M2 markers expression (CD206, IL-10). Administration of ferrostatin-1 completely abrogated these polarization shifts, confirming a ferroptosis-dependent mechanism. We established a robust transcriptome-wide prognostic tool and identified SNAI3-AS1 as a specific suppressor of glioma invasion. Furthermore, SNAI3-AS1 cooperates with ferroptosis induction to drive M1 macrophage polarization, offering a promising TME-remodeling therapeutic strategy.