Abstract
The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential component of the activation of the necroptotic pathway. Emerging evidence suggests that MLKL plays a key role in liver disease. However, how MLKL contributes to hepatocarcinogenesis has not been fully elucidated. Herein, we report that MLKL is upregulated in a diethylnitrosamine (DEN)-induced murine HCC model and is associated with human hepatocellular carcinomas. Hepatocyte-specific MLKL knockout suppresses the progression of hepatocarcinogenesis. Conversely, MLKL overexpression aggravates the initiation and progression of DEN-induced HCC. Mechanistic study reveals that deletion of MLKL significantly increases the activation of autophagy, thereby protecting against hepatocarcinogenesis. MLKL directly interacts with AMPKα1 and inhibits its activity independent of its necroptotic function. Mechanistically, MLKL serves as a bridging molecule between AMPKα1 and protein phosphatase 1B (PPM1B), thus enhancing the dephosphorylation of AMPKα1. Consistently, MLKL expression correlates negatively with AMPKα1 phosphorylation in HCC patients. Taken together, our findings highlight MLKL as a novel AMPK gatekeeper that plays key roles in inhibiting autophagy and driving hepatocarcinogenesis, suggesting that the MLKL-AMPKα1 axis is a potential therapeutic target for HCC.
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The authors declare that the data are present in the paper and/or the supplementary information. Additional data supporting the present study are available from the corresponding author upon reasonable request.
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Funding
This work was supported by the National Natural Science Foundation of China (81902852, 82003237), Natural Science Foundation of Hubei Province of China (2022CFB481), Natural Science Foundation of Hubei Provincial Department of Education (T2022021), Projects of International Cooperation and Exchanges (G2022027004L, G2022027012L) and the Advantages Discipline Group (Medicine) Project in Higher Education of Hubei Province (2021-2025) (2024XKQY26, 2024BMXKQY2). The authors appreciate Professor Quentin Qiang Liu and Professor Mian Wu for their helpful suggestions on this study. The authors thank the Biomedical Research Institute of Hubei University of Medicine for instrument support.
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XY and QZ conceived the project and designed the research studies. QZ, XY, MF, JG, and HW performed most of the experiments described. JY performed structure analysis. AZ, and JW provided help with animal and technical assistance in the mouse experiments. YH, ZS and YL provided conceptual advice and helpful discussion. XY, QZ and MF analyzed data. XY and QZ prepared the manuscript.
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The study was approved by the Science and Technology Ethics Committee of Hubei University of Medicine (No. 2023-EER-05). Animal experiments were approved by the the Animal Care and Use Committee of Hubei Medicine University (No. 2022-021) and animal care was conducted in accordance with institutional guidelines.
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Yu, X., Feng, M., Guo, J. et al. MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy. Cell Death Differ 31, 1085–1098 (2024). https://doi.org/10.1038/s41418-024-01314-5
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DOI: https://doi.org/10.1038/s41418-024-01314-5
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