Ferroptosis and low-grade Glioma: The breakthrough potential of NUAK2

Low-grade glioma (LGG) is a primary brain tumor with high cellular heterogeneity and recurrence, leading to poor prognosis. Standard treatments (surgery, radiotherapy, and chemotherapy) have limited efficacy. Ferroptosis, an iron-dependent form of regulated cell death, is a potential therapeutic target, while dysregulated ferroptosis-related genes (FRGs) may drive tumor progression and therapy resistance.

This study integrated multi-omics data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) to identify FRGs associated with LGG prognosis. Single-cell RNA sequencing (scRNA-seq) and pseudotime trajectory analysis were performed to investigate their functional roles. Key findings were validated through in vitro and in vivo experiments.

We identified 345 FRGs associated with LGG prognosis, which are involved in oxidative stress response, cell proliferation, and immune regulation. High-risk patients exhibited an immunosuppressive tumor microenvironment with elevated levels of M2 macrophages and Treg cells but reduced CD8⁺ T cell infiltration. Pseudotime trajectory analysis highlighted the dynamic roles of macrophages and astrocytes in immune evasion and microenvironment remodeling. Notably, the NUAK2 gene emerged as a key driver of tumor progression and immune suppression. In vitro and in vivo experiments confirmed that targeting NUAK2 significantly reduced tumor cell viability and growth, underscoring its critical regulatory role in LGG.

Our study provides comprehensive insights into the role of FRGs in LGG prognosis and tumor microenvironment regulation, with a particular focus on the NUAK2 gene. As a potential therapeutic target, NUAK2's critical role in tumor progression and immune evasion offers a new direction for LGG treatment. Future research should focus on validating NUAK2's role in larger cohorts and exploring its clinical application as a biomarker and therapeutic target.