CircMAN1A2 Levels Determine GBM Susceptibility to TMZ in a Pathway Involving TEP1- and KEAP1-Mediated NRF2 Degradation Leading to Ferroptosis

Abstract

Background: Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and resistance to temozolomide (TMZ). The role of downregulated circular RNAs (circRNAs) in GBM progression remains unclear.

Methods: CircRNA sequencing and public dataset analysis identified dysregulated circRNAs in GBM. Functional assays were conducted in patient-derived glioma stem-like cells (GSCs) with circMAN1A2 overexpression or knockdown. Ferroptosis-related experiments, protein interaction assays, and in vivo mouse models were used to explore mechanisms and therapeutic effects.

Results: CircMAN1A2 was significantly downregulated in GBM tissues and inversely correlated with WHO grade and patient survival. Overexpression of circMAN1A2 inhibited GSC proliferation, stemness, invasion, and reversed TMZ resistance by inducing ferroptosis. Mechanistically, circMAN1A2 was regulated by PRPF40B and directly bound to TEP1, disrupting its interaction with KEAP1, thereby promoting NRF2 degradation and ferroptosis. NRF2 upregulated ANXA1, which promoted tumor-associated macrophage (TAM) recruitment and M2 polarization. In vivo, circMAN1A2 overexpression suppressed tumor growth, enhanced TMZ sensitivity, and reduced NRF2/ANXA1 expression, effects reversed by TEP1.

Conclusions: CircMAN1A2 suppresses GBM progression and TMZ resistance by inducing ferroptosis and modulating the TEP1-KEAP1-NRF2-ANXA1 axis. It represents a potential therapeutic target in GBM.

Keywords: ANXA1; KEAP1‐NRF2 pathway; circRNA; glioma stem cells; tumor‐associated macrophages.