A BBB-permeable β
Cheng Wei, Chen Zhuoying, Liu Yani, Luo Xiangjie, Li Zheng, Yang Huiquan, Zhong Yifan, Cai Xinyi, Sun Zhigang, Zhou Ling, Zhang Bing, Zhu Hai-Liang, Li Minyong, Qian Yong
Abstract
β3-Adrenergic receptors (β3-ARs), as a subclass of G protein-coupled receptors (GPCRs), play a pivotal role in regulating oxidative stress. However, the dynamic interplay between their microenvironmental fluctuations and glioma mechanisms remains poorly understood. Here, we report the development of GSHP, a blood-brain barrier (BBB)-permeable probe that simultaneously visualizes β3-ARs and reversibly monitors the surrounding redox status in real-time. This dual-responsive probe enables reversible dynamic imaging of redox homeostasis around β3-ARs in living cells under stress conditions, providing direct visual evidence for redox adaptation. Using GSHP for high-throughput screening, we identified and validated baicalin as a potent β3-AR natural inhibitor that induces glutathione depletion and triggers oxidative stress-mediated apoptosis via the Gαi/o-extracellular signal-regulated kinase (ERK)-nuclear factor erythroid 2-related factor 2 (Nrf2)-glutamate-cysteine ligase catalytic subunit (GCLc) signaling pathway in U251 glioblastoma cells. In orthotopic U251 glioma mouse models, GSHP penetrated the brain and enabled dual-channel imaging of β3-AR overexpression and redox imbalance in vivo, allowing for effective glioma discrimination and demonstrating its potential for therapeutic monitoring. GSHP thus serves as a versatile platform for studying β3-AR-related redox biology and facilitating therapeutic discovery in brain diseases.
Key Findings
- Development of GSHP, a BBB-permeable probe that visualizes β3-ARs and monitors redox status in real-time.
- Identification of baicalin as a β3-AR natural inhibitor that induces glutathione depletion and oxidative stress-mediated apoptosis via the Gαi/o-ERK-Nrf2-GCLc signaling pathway in glioblastoma cells.
- GSHP enables dual-channel imaging of β3-AR overexpression and redox imbalance in vivo, facilitating glioma discrimination and therapeutic monitoring.
Clinical Significance
This study provides a novel tool for real-time imaging of redox dynamics related to β3-ARs in brain tumors and identifies a potential therapeutic compound, baicalin, highlighting new avenues for targeted oxidative stress-based glioma treatment.
Citation
Cheng Wei, Chen Zhuoying, Liu Yaniet al.. A BBB-permeable β Science advances. 2026-May-15.