Robust prediction of glioma prognosis by hypoxia-induced ferroptosis genes: VEGFA-XBP1 co-expression for salvage therapy

• Published in: Cancer biology & therapy Vol. 26; no. 1; p. 2529643
• Main Authors: Liwei, Zhou, Hanwen, Lu, Wenpeng, Zhao, Weijie, Yu, Sifang, Chen, Bingchang, Zhang, Zhangyu, Li, Xin, Gao, Wenhua, Li, Jianyao, Mao, Yuanyuan, Xie, Guowei, Tan, Zhanxiang, Wang
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.12.2025; Taylor & Francis Group
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - analysis; Biomarkers, Tumor - antagonists & inhibitors; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Brain Neoplasms - genetics; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Female; ferroptosis; Ferroptosis - drug effects; Ferroptosis - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; glioma; Glioma - genetics; Glioma - mortality; Glioma - pathology; Glioma - therapy; Humans; Hypoxia; immunity; Male; Middle Aged; Nomograms; prognosis; Research Paper; Risk Assessment - methods; Salvage Therapy - methods; Tumor Hypoxia - drug effects; Tumor Hypoxia - genetics; Vascular Endothelial Growth Factor A - analysis; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; X-Box Binding Protein 1 - analysis; X-Box Binding Protein 1 - antagonists & inhibitors; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism; Hypoxia; glioma; ferroptosis; immunity; prognosis
• ISSN: 1538-4047; 1555-8576; 1555-8576
• DOI: 10.1080/15384047.2025.2529643

Hypoxia as a hallmark of solid malignancies compromises therapeutic efficacy and prognosis. This study deciphers the functional role of hypoxia-induced ferroptosis in glioma prognosis. Hypoxia-related transcripts and ferroptosis markers were curated from public databases. ConsensusClusterPlus identify hypoxia-based molecular subtypes, while LASSO-penalized Cox regression integrated with limma-based differential expression analysis screened prognostic ferroptosis genes. Subsequent risk modeling was validated against clinical parameters and extended through nomogram construction. Protein-protein interaction networks centered on HIF-1αidentified high-confidence interactors, with parallel immune correlation analysis completing the systems-level investigation.Based on 27 hypoxia-associated genes, we stratified samples into three distinct hypoxic clusters. Differential analysis of 123 ferroptosis markers across clusters, combined with univariate Cox regression and LASSO regression, identified 23 hypoxia-induced ferroptosis genes for constructing a prognostic model. The model demonstrated robust predictive accuracy with AUC values of 0.80 (1-year), 0.86 (3-year), and 0.86 (5-year). GSEA revealed significant enrichment in ECM-receptor interactions, focal adhesion, JAK-STAT signaling, and p53 signaling pathways, suggesting their involvement in hypoxia-induced ferroptosis. Our risk model significantly outperformed conventional clinical parameters (pathology, grade, age, primary/recurrent status). Protein-protein interaction analysis incorporating HIF-1αand the 23-model genes identified XBP1 and VEGFA co-expression as significant positive prognostic factor. The immune infiltration analysis further indicated that M0 macrophages may participate in the regulation of the prognosis of VEGFA-XBP1.Hypoxia-induced ferroptosis modulation emerges as a prognostic factor in gliomas, with XBP1 and VEGFA representing druggable nodes for novel combination therapies.