Ferroptosis-related gene regulation and miRNA/lncRNA Network on Temozolomide Resistance in Glioblastoma

Abstract

Objectives: This study aimed to elucidate ferroptosis-associated transcriptomic and post-transcriptional regulatory networks underlying temozolomide (TMZ) resistance in glioblastoma (GBM) by integrating RNA-seq data with curated ferroptosis, microRNA (miRNA), and long non-coding RNA (lncRNA) interaction databases.

Materials and methods: We performed an integrative transcriptomic analysis of parental and TMZ-resistant U251 and U87 GBMcells to characterize ferroptosis-associated regulatory networks. Differential expression and enrichment analyses revealed distinct, cell line-specific ferroptosis-related transcriptional programs linked to TMZ resistance. By integrating curated ferroptosis genes with experimentally validated miRNA and lncRNA interactions, we constructed a high-confidence ferroptosis-centred competing endogenous RNA network.

Results: Ferroptosis-related differentially expressed genes associated with TMZ response were identified. Then, the top miRNAs and lncRNAs were determined to have the most regulatory connections with these genes. Key regulatory hubs, including miR-16-5p, miR-155-5p, KCNQ1OT1, and NEAT1, were identified as potential modulators of ferroptosis and TMZ resistance. We visualised key messenger RNA-miRNA-lncRNA pathways, such as KCNQ1OT1–miR-16-5p-CCND1/CDK6.

Conclusion: These findings highlight post-transcriptional regulatory layers underlying chemoresistance in GBM. Overall, this study provides important insights into the effect of TMZ on GBM cells via the ferroptosis axis.

Cite this article as: Gumusoglu-Acar E, Gunel T. Ferroptosis-related gene regulation and miRNA/lncRNA Network on Temozolomide Resistance in Glioblastoma. D J Med Sci 2025;11(3):122-133. doi: 10.5606/fng.btd.2025.210.