ABSTRACT Neuroinflammation driven by microglial activation is a defining feature of Alzheimer's disease (AD), yet the molecular mechanisms sustaining this proinflammatory state remain unclear. Here, we identify the deubiquitinase OTUD7B as a critical regulator of microglial activation and AD pathology. OTUD7B expression was markedly elevated in microglia from AD mouse models and human patient datasets. Genetic ablation of OTUD7B markedly attenuated microglial activation and cytokine release, alleviated neuronal injury, and improved cognitive performance in AD mice. Mechanistically, OTUD7B directly interacted with STAT3 and removed K48‐linked ubiquitin chains at lysine 283, thereby stabilizing STAT3, promoting its nuclear translocation, and enhancing transcription of proinflammatory mediators. Integrative transcriptomic analysis revealed that OTUD7B deficiency suppressed proinflammatory transcriptional programs in microglia. Together, these findings uncover an OTUD7B‐STAT3 signaling axis that sustains microglial‐driven neuroinflammation and identify OTUD7B as a potential therapeutic target for mitigating neurodegenerative pathology in AD.
Luyao Li, Hao Tang, Qin Yu et al.· Advancement of science· 0 citations
Voltage-gated sodium channels (VGSCs/Navs) are essential targets for the treatment of numerous neurological, muscular, and cardiac disorders. Despite the increasing clinical interest in subtype-selective modulators, current public databases provide fragmented and inconsistent information on VGSC-related compounds and targets, particularly lacking coverage on peptides. To address this limitation, we developed NavDB, a specialized and open-access database focusing on VGSC modulators and targets. NavDB integrates 8023 curated data records covering 5168 compounds, including small molecules, toxins, drugs, and peptides, along with comprehensive annotations on biological activity, druggability, and structural feature. NavDB also features advanced functions such as text-based and structure-based search, peptide similarity matching, and AI-powered property prediction. Moreover, the database offers high-quality 3D visualizations of targets and peptides, with disulfide bond and signal peptide annotations. All data are freely downloadable to support both experimental and computational drug discovery. NavDB is publicly available at: http://cadd.zju.edu.cn/navdb/.
Gaoang Wang, Jiahui Yu, Haiyi Chen et al.· Journal of Chemical Informat...· 0 citations