Dual suppression of stemness and redox adaptation in glioblastoma through filaggrin upregulation by an abiraterone-based HDAC inhibitor

BACKGROUND: -methylguanine-DNA methyltransferase (MGMT) overexpression, glioma stem cell (GSC) persistence, and redox adaptation. METHODS: We developed cp8, a first-in-class abiraterone-based histone deacetylase (HDAC) inhibitor, to simultaneously target these resistance mechanisms. The orthotopic mouse models were used to evaluate the efficacy of cp8 compared to SAHA (vorinostat). The mouse survival period was recorded, and the tumor growth was monitored using the IVIS imaging system. RESULTS: Cp8 demonstrated approximately tenfold greater potency than SAHA, with IC₅₀ values ≤ 3 µM against TMZ-resistant GBM cells (compared with ≥ 30 µM for SAHA). Transcriptomic analysis revealed a unique ability of cp8 to upregulate filaggrin (FLG), a structural protein whose expression correlated with improved patient survival in TCGA and CGGA datasets (p = 0.001). Functional studies showed that FLG knockdown increased GSC-associated markers (Oct4, 2.1-fold; SOX2, 1.8-fold) and enhanced TMZ resistance, whereas cp8 treatment reduced MGMT protein expression by 68% and significantly decreased glioma sphere size by 54% (p < 0.01). In orthotopic models, cp8 extended median survival to 59 days compared with 34 days for controls (p < 0.001) and 49 days for SAHA (p < 0.01), while reducing tumor volume by 72% (p < 0.001) without systemic toxicity. Mechanistically, dual inhibition of HDAC6 and CYP17A1 by cp8 disrupted redox homeostasis and stemness-associated pathways, leading to altered ROS metabolism, reduced MGMT expression, and attenuation of GSC-driven tumor growth while restoring FLG-mediated tumor suppression. CONCLUSION: This study establishes FLG as a novel therapeutic target in GBM and validates the suppressive efficacy of cp8 on the characteristics of TMZ resistance, highlighting the translational potential as a multitargeted therapy against TMZ-resistant GBM.