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Lookup NU author(s): Dr Xiaowen (Shirley) MaORCiD
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© 2025 The Author(s).Introduction Transcription factor EB (TFEB) deficiency contributes to insufficient autophagic degradation, resulting in zymogen granule (ZG) accumulation and subsequent premature activation, which underlies the pathogenesis of alcoholic pancreatitis (AP). Despite this mechanistic insight, pharmacological activation of TFEB via plant-derived agents remains an underdeveloped therapeutic avenue. Objectives This study aims to investigate Wogonin’s role as a key Scutellaria baicalensis (Huangqin, HQ) component in protecting against AP, with specific focus on TFEB-mediated autophagy activation. Methods Using TFEB-AcGFP and mRFP-GFP-LC3 reporter systems, we assessed Wogonin-enriched HQ extracts on TFEB nuclear translocation and autophagic flux. Pharmacological and genetic approaches were combined to established HQ/Wogonin’s effects on alcohol-induced pancreatic injury through TFEB-mediated autophagic restoration. Structure-based virtual screening and molecular docking techniques were employed to predict the binding activity of Wogonin with upstream kinases regulating TFEB. Prioritized interactions underwent biophysical validation via surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and cellular thermal shift assay (CETSA) assays. Results HQ/Wogonin enhanced TFEB nuclear translocation and transcriptional activity, thereby restoring autophagic degradation to exert protection against alcohol-induced ZG accumulation and pancreatic injuries. Acinar TFEB knockout abolished HQ’s protective effects against AP. Mechanistic studies revealed Wogonin directly bound with AMPK (AMP-activated protein kinase) to promote its protein stability, leading to improved TFEB activation. Conclusion This study establishes Wogonin as the pivotal bioactive driver behind HQ’s therapeutic efficacy, orchestrating AMPK-TFEB-autophagy coordination to mitigate AP. Atomic-level resolution of Wogonin’s adenine-mimetic binding to AMPK provides novel therapeutic strategies for developing kinase-stabilizing botanicals targeting TFEB activation to treat pancreatitis.
Author(s): Qin Z, Sun X, Zeng J, Li G, Wang H, Chen S, Tan S, An L, Wang C, Wang L, Wang J, Ma X, Zhao Z, Chao X, Liu Z, Wang S
Publication type: Article
Publication status: Published
Journal: Journal of Advanced Research
Year: 2025
Pages: Epub ahead of print
Online publication date: 10/11/2025
Acceptance date: 06/11/2025
ISSN (print): 2090-1232
ISSN (electronic): 2090-1224
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.jare.2025.11.006
DOI: 10.1016/j.jare.2025.11.006
PubMed id: 41223988
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