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

## TL;DR

A new brain-targeted curcumin analog, DMC-GF, inhibits glioblastoma growth by modulating a key signaling pathway involving THBS1, TGF-β1, and PI3K–AKT.

## Contribution

This study is the first to show that DMC-GF inhibits GBM progression via THBS1/TGF-β1/PI3K–AKT axis modulation.

## Key findings

- DMC-GF inhibits GBM cell proliferation, migration, and invasion while promoting apoptosis.
- THBS1 is a key target of DMC-GF, and its suppression leads to inhibition of the TGF-β1/PI3K–AKT pathway.
- THBS1 knockdown mimics DMC-GF's anti-tumor effects, and THBS1 overexpression reduces these effects.

## Abstract

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.