Fudan team develops a novel CRG-based classification model for IDH1-mutant gliomas, advancing precision therapy optimization

Glioma, the most common primary malignant tumor of the central nervous system, presents significant clinical challenges due to its pronounced intratumoral heterogeneity and poor prognosis. Notably, isocitrate dehydrogenase 1 (IDH1) mutations occur in over 70% of WHO grade II–III gliomas. While patients with IDH1-mutant gliomas generally have better survival outcomes than those with wild-type tumors, substantial heterogeneity within this subgroup remains poorly understood, highlighting the urgent need for personalized therapeutic strategies.

To address this gap, a research team led by Minfeng Shu, Yilin Wang and Qimeng Chang from Fudan University published a study titled "Integrated Analysis of Cuproptosis Regulators Reveals Prognostic Significance and Therapeutic Targets in IDH1-Mutant Glioma" in MedComm - Future Medicine. This study integrates cuproptosis regulatory networks into the molecular subtyping of IDH1-mutant gliomas, successfully constructing a prognostic model with clinical translational value.

Cuproptosis, a recently identified form of programmed cell death, is driven by copper ion-induced mitochondrial dysfunction and aberrant lipoylated protein aggregation. The researchers identified 11 cuproptosis-related genes (CRGs) and, through consensus clustering, classified IDH1-mutant gliomas into two novel subtypes. Subtype G1, characterized by high CRG expression and an immunosuppressive tumor microenvironment, was associated with significantly worse clinical outcomes compared to Subtype G2.

Further analyses identified FDX1 and SLC31A1 as key regulators. Experimental validation confirmed their overexpression in malignant glioma cells, their strong association with IDH1 mutation status, and their role in immune evasion by upregulating immune checkpoint molecules. The FDX1/SLC31A1-based risk model demonstrated superior prognostic performance across multiple independent cohorts, outperforming existing models.

Therapeutically, high-risk patients exhibited increased sensitivity to alkylating agents and platinum-based chemotherapy but reduced responsiveness to immune checkpoint inhibitors, suggesting that cuproptosis-associated molecular features could inform chemotherapy selection. Additionally, the study proposed a COX10-AS1/miR-1-3p/FDX1-SLC31A1 regulatory axis, revealing a potential strategy to overcome treatment resistance by targeting cuproptosis pathways.

In conclusion, this study establishes a cuproptosis-based molecular subtyping system for IDH1-mutant gliomas and advances clinical translation in three key aspects: prognostic stratification, chemotherapy response prediction, and mechanistic insights into immune evasion. These findings lay a critical foundation for developing personalized therapeutic strategies.