Abstract
<title>Abstract</title> <p> <bold>Background:</bold> Proneural-mesenchymal transition (PMT), a glioblastoma (GBM)-specific process driving tumor progression, has not been linked to ferroptosis susceptibility in GBM. In contrast, invasive tumor cells exhibit ferroptosis sensitivity in carcinomas, highlighting the unexplored role of GBM-specific PMT in ferroptosis regulation. While circular RNAs (circRNAs) contribute to GBM pathogenesis, their functional role in PMT is undefined. <bold>Methods</bold> : RNA-seq data from clinical specimens of 50 GBM patients were used to calculate mesenchymal (MES) and proneural (PN) enrichment scores, with the most differentially expressed circRNA (circLMF1) identified via circular RNA sequencing. The functional roles of circLMF1 in PMT and ferroptosis were evaluated in vitro and in vivo through proliferation (CCK-8, EdU), migration (transwell), stemness (neurosphere formation, ELDA), expression of PN/MES markers, and ferroptosis assays (GSH/MDA quantification, BODIPY C11 staining, TEM). Molecular mechanisms were validated using RNA pull-down, RIP, ChIP, dual-luciferase reporter assays, Co-IP, and ubiquitination assays. <bold>Results</bold> : This study identifies circLMF1 as a carcinogenic factor that is markedly upregulated in MES-type GBM and promotes PMT in GBM. However, we demonstrate that circLMF1 also enhances the sensitivity of GSCs to ferroptosis during PMT. Mechanistically, circLMF1 binds TFE3 and blocks SMURF1-mediated K48-linked ubiquitination, stabilizing TFE3 to transcriptionally upregulate MVP and ABCC1 expression, thereby promoting PMT and enhancing ferroptosis sensitivity. <bold>Conclusion</bold> : CircLMF1 drives GBM malignancy through the PMT pathway, concurrently enhancing the sensitivity of GSCs to ferroptosis. This mechanistic effect unveils a therapeutic vulnerability that can be exploited via combinatorial targeting of the CircLMF1-PMT axis, converting GSCs' aggressive phenotype into a treatable liability. </p>