Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

Autor: Fu JT; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China., Liu J; Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China., Wu WB; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China., Chen YT; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China., Lu GD; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China., Cao Q; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China; National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University/Second Military Medical University, Shanghai, China., Meng HB; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Tong J; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Zhu JH; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Wang XJ; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Liu Y; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Zhuang C; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China; National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University/Second Military Medical University, Shanghai, China., Sheng C; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China; National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University/Second Military Medical University, Shanghai, China., Shen FM; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Liu X; Department of Pathogen Biology, Second Military Medical University, Shanghai, China., Wang H; Department of Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China., Yu Y; School of Medicine, Shanghai University, Shanghai, China., Zhang Y; School of Medicine, Shanghai University, Shanghai, China., Liang HY; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China; National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University/Second Military Medical University, Shanghai, China., Zhang JB; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China; National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University/Second Military Medical University, Shanghai, China., Li DJ; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Li X; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China; National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University/Second Military Medical University, Shanghai, China. Electronic address: xiangli@smmu.edu.cn., Wang ZB; Department of Critical Care Medicine, School of Anesthesiology, Naval Medical University, Shanghai, China. Electronic address: methyl@smmu.edu.cn., Wang P; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University/Second Military Medical University, Shanghai, China; National Demonstration Center for Experimental Pharmaceutical Education, Naval Medical University/Second Military Medical University, Shanghai, China. Electronic address: pwang@smmu.edu.cn.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2024 Sep; Vol. 81 (3), pp. 389-403. Date of Electronic Publication: 2024 Apr 25.
DOI: 10.1016/j.jhep.2024.04.009
Abstrakt: Background & Aims: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH.
Methods: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target.
Results: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4 + resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4 + /CD8 + T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice.
Conclusion: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment.
Impact and Implications: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.
(Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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