Xi Y, Guo D, Li S, Guo JY, Chen XZ, Tang JF, Zhou CF. Targeting mixed lineage kinase domain-like protein's non-necroptosis role: A new horizon in anti-inflammatory therapy for alcoholic liver disease. World J Gastroenterol 2025; 31(13): 104546 [DOI: 10.3748/wjg.v31.i13.104546]
Corresponding Author of This Article
Ce-Fan Zhou, School of Life and Health Sciences, Institute of Biomedical Research, National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, No. 28 Nanli Road, Wuhan 430068, Hubei Province, China. cefan@hbut.edu.cn
Research Domain of This Article
Biology
Article-Type of This Article
Letter to the Editor
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Yue Xi, Dong Guo, Shi Li, Jie-Yu Guo, Jing-Feng Tang, Ce-Fan Zhou, School of Life and Health Sciences, Institute of Biomedical Research, National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, Hubei Province, China
Xing-Zhen Chen, Department of Physiology, University of Alberta, Edmonton, AB T6G 2R3, Canada
Co-first authors: Yue Xi and Dong Guo.
Co-corresponding authors: Jing-Feng Tang and Ce-Fan Zhou.
Author contributions: Xi Y and Guo D contributed equally to this study as co-first authors; Tang JF and Zhou CF contributed equally to this study as co-corresponding authors; Xi Y prepared the original draft; Zhou CF and Guo D contributed to the conceptualization, writing, review and editing of the manuscript; Xi Y, Li S, Zhou CF and Tang JF collaboratively drafted the manuscript; Guo JY and Chen XZ provided some valuable opinions; all authors have reviewed and approved the final version of the manuscript.
Conflict-of-interest statement: Dr. Zhou has nothing to disclose.
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: Ce-Fan Zhou, School of Life and Health Sciences, Institute of Biomedical Research, National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, No. 28 Nanli Road, Wuhan 430068, Hubei Province, China. cefan@hbut.edu.cn
Received: December 24, 2024 Revised: February 25, 2025 Accepted: March 6, 2025 Published online: April 7, 2025 Processing time: 99 Days and 22.8 Hours
Abstract
Although mixed lineage kinase domain-like protein (MLKL) is widely recognized as a critical effector in the necroptotic signaling pathway, MLKL plays broader regulatory roles beyond programmed necroptosis. Notably, Xuan Yuan et al demonstrated that CPD4, an ATP-binding pocket inhibitor of MLKL, significantly reduces liver inflammation and improves liver function by inhibiting NF-κB signaling, suggesting its use as a potential therapeutic candidate for alcoholic liver disease. However, the pharmacokinetic properties and long-term toxicity of CPD4 require further evaluation. Moreover, a single therapeutic strategy targeting MLKL may not be sufficient. Future studies should focus on the precise regulation of MLKL and develop combination therapies to achieve dual intervention of inflammatory and cell death pathways. This paper provides an important theoretical foundation for translational research on MLKL-targeted therapy. However, its clinical translation requires overcoming existing limitations and further elucidating the regulatory network of MLKL in complex microenvironments.
Core Tip: The mixed lineage kinase domain-like protein (MLKL) ATP-binding pocket inhibitor CPD4 demonstrates significant promise as a novel therapeutic agent for alcoholic liver disease (ALD), providing dual benefits through the reduction of hepatic inflammation and the enhancement of liver function. In this article, we emphasize the regulatory role of CPD4 as a targeted inhibitor of the MLKL ATP-binding pocket and highlight its ability to modulate ALD progression through the NF-κB signaling pathway. Furthermore, future research should explore the potential of combination therapies involving MLKL inhibitors to optimize treatment strategies. These advancements may pave the way for personalized approaches to treating ALD and other related liver diseases.
