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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Bicuculline ameliorates metabolic dysfunction-associated steatotic liver disease by inhibiting the nuclear factor-kappa B pathway and reducing lipid accumulation
Xiao-Mei Wang, Ze Dai, Dai-Jun Lu, Chao-Qun Bao, Nai-Bin Yang, Yu-Ping Zhou
Xiao-Mei Wang, Dai-Jun Lu, Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
Xiao-Mei Wang, Ze Dai, Dai-Jun Lu, Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
Chao-Qun Bao, Yu-Ping Zhou, Department of Traditional Chinese Medicine, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
Nai-Bin Yang, Department of Hepatology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
Yu-Ping Zhou, Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
Yu-Ping Zhou, Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
Author contributions: Zhou YP designed and coordinated the study; Wang XM, Dai Z, Lu DJ and Bao CQ performed the experiments and acquired and analyzed the data; Wang XM, Dai Z and Yang NB interpreted the data; Wang XM and Lu DJ wrote the manuscript; All the authors approved the final version of the article.
Supported by Joint TCM Science & Technology Projects of National Demonstration Zones for Comprehensive TCM Reform, No. GZY-KJS-ZJ-2025-044; and Ningbo Top Medical and Health Research Program, No. 2023020612.
Institutional animal care and use committee statement: The animal study protocol was approved by the Ethics Committee of the Animal Experiment Center of Ningbo University (No. NBU20230320 April 30, 2023) for studies involving animals.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Yu-Ping Zhou, PhD, Department of Traditional Chinese Medicine, The First Affiliated Hospital of Ningbo University, No. 247 Renmin Road, Jiangbei District, Ningbo 315020, Zhejiang Province, China.
fyzhouyuping@nbu.edu.cn
Received: February 2, 2025
Revised: March 31, 2025
Accepted: April 21, 2025
Published online: May 7, 2025
Processing time: 89 Days and 1.6 Hours
BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a prominent and pervasive global health challenge. Bicuculline (BIC), which is a key active component of the anti-MASLD prescription "Eight Zhes Decoction", has been preliminarily shown by our research team to have significant potential in treating MASLD.
AIM
To determine BIC's efficacy in treating MASLD by regulating lipid metabolism and suppressing hepatic inflammation via nuclear factor-kappa B (NF-κB) pathway, identifying it as a therapeutic candidate.
METHODS
This study explored the potential of BIC in preventing and treating MASLD using zebrafish, cellular (HepG2 and AML12), and mouse models.
RESULTS
Our results indicate that BIC significantly reduces lipid accumulation and inflammation both in vivo and in vitro. Transcriptomic analysis suggested that the anti-MASLD effects of BIC are linked to the inhibition of the NF-κB pathway, which plays a critical role in mitigating inflammation and lipid deposition.
CONCLUSION
This study is the first to demonstrate that BIC specifically alleviates lipid accumulation and hepatic steatosis in MASLD models via the NF-κB signaling pathway. Overall, BIC has emerged as a promising candidate for treating MASLD.
Core Tip: This study identifies bicuculline (BIC) as a novel agent for treating metabolic dysfunction-associated steatotic liver disease (MASLD), demonstrating for the first time the dual efficacy of BIC in reducing hepatic lipid accumulation and inflammation via nuclear factor-kappa B (NF-κB) pathway inhibition. Experiments involving zebrafish, mouse, and cellular (HepG2 and AML12) models confirmed that, mechanistically, BIC disrupts the NF-κB signaling pathway, which is a central hub that links metabolic dysfunction and inflammation in MASLD. Transcriptomic insights confirm pathway-specific targeting, distinguishing BIC from broad-spectrum therapies. These findings not only reveal a new axis that can be targeted in the treatment of MASLD but also position BIC as a precision therapeutic candidate with translational promise. The multimodel validation highlights the robustness of BIC, advancing this agent toward clinical exploration.
