Sorafenib promotes the E3 ubiquitin ligase FBXW7 to increase tau degradation and ameliorate tauopathies.
10.1016/j.apsb.2025.09.024
- Author:
Yunqiang ZHOU
1
;
Yong WANG
1
;
Huiying YANG
2
;
Chi ZHANG
1
;
Jian MENG
1
;
Lingliang ZHANG
1
;
Kun LI
1
;
Ling-Ling HUANG
1
;
Xian ZHANG
1
;
Hong LUO
1
;
Yunwu ZHANG
1
Author Information
1. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen 361102, China.
2. Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China.
- Publication Type:Journal Article
- Keywords:
Alzheimer's disease;
FBXW7;
Sorafenib;
Tau;
Tauopathy;
Ubiquitin-proteasome pathway
- From:
Acta Pharmaceutica Sinica B
2025;15(11):5817-5831
- CountryChina
- Language:English
-
Abstract:
Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin-proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.
