Hepatocyte-Targeted Lipid Nanoparticle Delivery of HERC2 Plasmid Controls Drug-Induced Hepatotoxicity by Limiting β-Catenin-Regulated CYP2E1 Expression.

Autor: Liu Y; Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China.; Clinical Oncology Center, Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China.; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China., Xu Q; Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China.; Department of Precision Laboratory, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 510180, China., Liu Y; Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China., Cao S; Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China.; Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, 999077, China., Luo J; Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China.; Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China., Zheng Z; Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China.; Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510080, China.; Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China., Zhou J; Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China., Lu X; Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China., Zhang L; Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China., Tan Y; Clinical Oncology Center, Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China.; Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, Guangdong, 516001, China., Chen Q; Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510080, China., Zuo D; Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China.; Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Dec; Vol. 11 (46), pp. e2401633. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1002/advs.202401633
Abstrakt: Understanding the molecular mechanisms that bridge hepatic inflammation and liver injury is crucial for developing effective therapeutic strategies for drug-induced liver injury (DILI) management. HECT domain and RCC1-like domain 2 (HERC2) belongs to the large Herc family of ubiquitin E3 ligases, which are implicated in tissue development and inflammation. The observation reveals a pronounced HERC2 expression in specific hepatocyte subsets that proliferate in response to DILI in humans, prompting an investigation into the role of HERC2 in distinct DILI progression. Under the APAP challenge, liver-specific HERC2-deficient mice suffer more severe liver damage. Integrated single-cell RNA sequencing analysis unveils a negative correlation between HERC2 and CYP2E1, a vital metabolic enzyme for xenobiotics, in hepatocytes from APAP-challenged mice. Mechanistically, HERC2 interacts with β-catenin to promote its ubiquitination, thereby governing CYP2E1 transcriptional regulation. Targeted hepatic delivery of lipid nanoparticle-encapsulated HERC2-overexpressing plasmid markedly reduces liver damage caused by APAP overdose. Collectively, these findings elucidate a previously unrecognized protective role of HERC2 in protecting against acute liver injury associated with drug metabolism disorders, highlighting its potential as a therapeutic target in treating DILI.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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