A Brain‐Targeting Curcumin Analog Inhibits Glioblastoma Progression Through THBS1/TGF‐β1/PI3K–AKT Axis Modulation: Evidence From Experimental and Bioinformatic Analyses

Glioblastoma (GBM) is the most aggressive primary brain tumour, associated with a dismal prognosis and an urgent need for innovative therapeutic strategies. To address this challenge, our group developed DMC-GF, a novel brain-targeted curcumin analog engineered to enhance blood-brain barrier permeability by blocking metabolic sites and improving GLUT1 recognition. Although its activity against glioma stem cells has been reported, the direct mechanisms by which DMC-GF acts on GBM cells remain unclear. In this study, we systematically investigated the molecular actions of DMC-GF using phenotypic assays, transcriptome sequencing, and bioinformatics analysis. DMC-GF exerted dose-dependent inhibitory effects on GBM cell proliferation, migration and invasion and concurrently promoted apoptosis, as reflected by reduced Bcl-2 expression, activation of Bax/Caspase-3 and reversal of epithelial-mesenchymal transition (E-cadherin↑, N-cadherin↓, MMP-3↓). Transcriptomic profiling identified THBS1 as a key downstream target, showing marked suppression following DMC-GF treatment. Functional experiments further confirmed that THBS1 knockdown mimics the anti-tumour effects of DMC-GF, whereas THBS1 overexpression partially mitigates its inhibitory actions. Mechanistic studies revealed that DMC-GF suppresses the non-canonical, Smad-independent TGF-β1 pathway by downregulating THBS1, thereby inhibiting PI3K/AKT signalling, as reflected by reduced phosphorylation of AKT, GSK3β and mTOR. Collectively, this work provides the first evidence that DMC-GF exerts anti-GBM effects through modulation of the THBS1/TGF-β1/PI3K-AKT axis. These findings suggest DMC-GF as a compelling brain-targeted therapeutic candidate, providing new mechanistic insights and a potential clinical strategy to overcome therapeutic resistance in GBM.