肝细胞特异性MET缺失加剧对乙酰氨基酚诱导的小鼠肝毒性。

IF 3.6 2区 医学 Q1 PATHOLOGY
Siddhi Jain, Ranjan Mukherjee, Gillian Williams, Jia-Jun Liu, Lanuza A P Faccioli, Zhiping Hu, Rodrigo M Florentino, George K Michalopoulos, Alejandro Soto-Gutierrez, Silvia Liu, Joseph Locker, Bharat Bhushan
{"title":"肝细胞特异性MET缺失加剧对乙酰氨基酚诱导的小鼠肝毒性。","authors":"Siddhi Jain, Ranjan Mukherjee, Gillian Williams, Jia-Jun Liu, Lanuza A P Faccioli, Zhiping Hu, Rodrigo M Florentino, George K Michalopoulos, Alejandro Soto-Gutierrez, Silvia Liu, Joseph Locker, Bharat Bhushan","doi":"10.1016/j.ajpath.2025.09.010","DOIUrl":null,"url":null,"abstract":"<p><p>Despite the well-known role of MET in liver regeneration following partial-hepatectomy (PHx), its role in the clinically-relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from PHx because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET-KO mice were given a toxic-dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated initial hepatotoxicity and consequentially impaired compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced JNK-activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative-damage, releasing cell-death inducer AIF into cytosol. Excess JNK-activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET-signaling. Pharmacological-activation of AKT reduced JNK-activation and hepatotoxicity in MET-KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling, but also activation of cell-death/senescence pathways along with impaired unfolded-protein-response in MET-KO mice. Analysis of published single-nucleus RNA-sequencing data showed proliferation in livers from APAP-induced ALF patients was associated with strong activation of HGF/MET signaling in hepatocytes, with spatial-transcriptomics showing striking induction of HGF surrounding the necrotic-zones. Interestingly, 35% of the genes altered in human-ALF were regulated by MET in the mouse AILI-model. In conclusion, present study demonstrates that MET is crucial for restraining hepatotoxicity following APAP overdose, via inhibiting mitochondrial cell-death signaling pathway.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hepatocyte-specific MET deletion exacerbates acetaminophen-induced hepatotoxicity in mice.\",\"authors\":\"Siddhi Jain, Ranjan Mukherjee, Gillian Williams, Jia-Jun Liu, Lanuza A P Faccioli, Zhiping Hu, Rodrigo M Florentino, George K Michalopoulos, Alejandro Soto-Gutierrez, Silvia Liu, Joseph Locker, Bharat Bhushan\",\"doi\":\"10.1016/j.ajpath.2025.09.010\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Despite the well-known role of MET in liver regeneration following partial-hepatectomy (PHx), its role in the clinically-relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from PHx because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET-KO mice were given a toxic-dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated initial hepatotoxicity and consequentially impaired compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced JNK-activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative-damage, releasing cell-death inducer AIF into cytosol. Excess JNK-activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET-signaling. Pharmacological-activation of AKT reduced JNK-activation and hepatotoxicity in MET-KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling, but also activation of cell-death/senescence pathways along with impaired unfolded-protein-response in MET-KO mice. Analysis of published single-nucleus RNA-sequencing data showed proliferation in livers from APAP-induced ALF patients was associated with strong activation of HGF/MET signaling in hepatocytes, with spatial-transcriptomics showing striking induction of HGF surrounding the necrotic-zones. Interestingly, 35% of the genes altered in human-ALF were regulated by MET in the mouse AILI-model. In conclusion, present study demonstrates that MET is crucial for restraining hepatotoxicity following APAP overdose, via inhibiting mitochondrial cell-death signaling pathway.</p>\",\"PeriodicalId\":7623,\"journal\":{\"name\":\"American Journal of Pathology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-09-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ajpath.2025.09.010\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ajpath.2025.09.010","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

尽管MET在部分肝切除术(PHx)后肝脏再生中的作用众所周知,但其在临床相关的对乙酰氨基酚(APAP)诱导的肝损伤(AILI)模型中的作用仍未被探索。aii明显不同于PHx,因为它与大量肝坏死有关。本研究旨在明确MET在AILI中的作用。给肝细胞特异性MET-KO小鼠注射毒性剂量的APAP,并评估肝损伤/再生参数。MET缺失显著加剧了最初的肝毒性,并因此损害了代偿性增殖反应,最终导致显著的死亡率。在机制上,MET缺失增强了jnk活化及其线粒体易位,导致线粒体过度氧化损伤,将细胞死亡诱导剂AIF释放到细胞质中。过量的JNK激活归因于AKT在缺乏met信号的情况下对JNK的抑制活性降低。AKT的药理激活降低了MET-KO小鼠的jnk激活和肝毒性。rna测序/免疫印迹不仅显示MET-KO小鼠的增殖/生存信号被抑制,而且细胞死亡/衰老途径被激活,同时未折叠蛋白反应受损。对已发表的单核rna测序数据的分析显示,apap诱导的ALF患者肝脏中的增殖与肝细胞中HGF/MET信号的强烈激活有关,空间转录组学显示坏死区周围HGF的显著诱导。有趣的是,在小鼠aili模型中,人类alf中35%的基因改变受到MET的调节。总之,本研究表明MET通过抑制线粒体细胞死亡信号通路,对抑制APAP过量后的肝毒性至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hepatocyte-specific MET deletion exacerbates acetaminophen-induced hepatotoxicity in mice.

Despite the well-known role of MET in liver regeneration following partial-hepatectomy (PHx), its role in the clinically-relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from PHx because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET-KO mice were given a toxic-dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated initial hepatotoxicity and consequentially impaired compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced JNK-activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative-damage, releasing cell-death inducer AIF into cytosol. Excess JNK-activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET-signaling. Pharmacological-activation of AKT reduced JNK-activation and hepatotoxicity in MET-KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling, but also activation of cell-death/senescence pathways along with impaired unfolded-protein-response in MET-KO mice. Analysis of published single-nucleus RNA-sequencing data showed proliferation in livers from APAP-induced ALF patients was associated with strong activation of HGF/MET signaling in hepatocytes, with spatial-transcriptomics showing striking induction of HGF surrounding the necrotic-zones. Interestingly, 35% of the genes altered in human-ALF were regulated by MET in the mouse AILI-model. In conclusion, present study demonstrates that MET is crucial for restraining hepatotoxicity following APAP overdose, via inhibiting mitochondrial cell-death signaling pathway.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信