MOTS-c Protects Against Acetaminophen-induced Liver Injury through the MAPK Signaling Pathway.

IF 2.5 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Protein and Peptide Letters Pub Date : 2026-01-01 DOI:10.2174/0109298665430028251230103831

Nan Li, Yimin Xu, Qixin Chen, Jinhong Jiang, Wei Wei Li

{"title":"MOTS-c Protects Against Acetaminophen-induced Liver Injury through the MAPK Signaling Pathway.","authors":"Nan Li, Yimin Xu, Qixin Chen, Jinhong Jiang, Wei Wei Li","doi":"10.2174/0109298665430028251230103831","DOIUrl":null,"url":null,"abstract":"Objective: Acetaminophen (APAP)-induced liver injury (AILI) is a leading cause of acute liver failure worldwide, but effective therapeutic strategies are still lacking. MOTS-c, a mitochondrial-derived peptide, has demonstrated hepatoprotective properties in models of nonalcoholic steatohepatitis (NASH) and hepatitis B virus (HBV) infection. This study aims to explore the role and underlying mechanisms of MOTS-c in AILI.Methods: An AILI model was established in male C57BL/6 mice via intraperitoneal (i.p.) injection of APAP (300 mg/kg). The therapeutic potential of MOTS-c and its mechanisms were assessed using behavioral tests, qPCR, western blotting, ELISA, immunohistochemistry, immunofluorescence, and TUNEL staining.Results: MOTS-c levels in both plasma and liver tissues were significantly reduced in APAPinduced AILI mice compared with controls. Administration of MOTS-c via i.p. injection markedly attenuated APAP-induced increases in AST and ALT levels, histopathological liver damage, and other liver injury markers. MOTS-c treatment suppressed the release of pro-inflammatory factors (TNF-α, IL-1β, IL-6, and COX-2) and macrophage infiltration induced by APAP. Furthermore, MOTS-c treatment significantly restored GSH content, diminished reactive oxygen species (ROS) production, and oxidative stress. TUNEL staining confirmed that increased apoptosis in APAPtreated livers was significantly attenuated by MOTS-c, which are key contributors to hepatocyte death and liver injury. Mechanistic studies revealed that MOTS-c inhibited APAP-induced phosphorylation of MAPK pathway components, including ERK, JNK, and p38. The protective effects of MOTS-c on serum ALT and AST levels were abolished by co-treatment with inhibitors of ERK, JNK, and p38.Discussion: This study reveals that the mitochondrial peptide MOTS-c can alleviate drug-induced liver injury by suppressing oxidative stress and inflammation via the MAPK pathway. This positions MOTS-c as a promising therapeutic candidate for treating APAP-induced liver injury.Conclusion: This study demonstrates that administering MOTS-c effectively protects against APAP-induced liver injury in mice. The protective mechanism involves suppressing the damaging MAPK signaling pathway (ERK, JNK, p38), which in turn reduces oxidative stress, inflammation, and cell death.","PeriodicalId":20736,"journal":{"name":"Protein and Peptide Letters","volume":" ","pages":"309-324"},"PeriodicalIF":2.5000,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Protein and Peptide Letters","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.2174/0109298665430028251230103831","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective: Acetaminophen (APAP)-induced liver injury (AILI) is a leading cause of acute liver failure worldwide, but effective therapeutic strategies are still lacking. MOTS-c, a mitochondrial-derived peptide, has demonstrated hepatoprotective properties in models of nonalcoholic steatohepatitis (NASH) and hepatitis B virus (HBV) infection. This study aims to explore the role and underlying mechanisms of MOTS-c in AILI.

Methods: An AILI model was established in male C57BL/6 mice via intraperitoneal (i.p.) injection of APAP (300 mg/kg). The therapeutic potential of MOTS-c and its mechanisms were assessed using behavioral tests, qPCR, western blotting, ELISA, immunohistochemistry, immunofluorescence, and TUNEL staining.

Results: MOTS-c levels in both plasma and liver tissues were significantly reduced in APAPinduced AILI mice compared with controls. Administration of MOTS-c via i.p. injection markedly attenuated APAP-induced increases in AST and ALT levels, histopathological liver damage, and other liver injury markers. MOTS-c treatment suppressed the release of pro-inflammatory factors (TNF-α, IL-1β, IL-6, and COX-2) and macrophage infiltration induced by APAP. Furthermore, MOTS-c treatment significantly restored GSH content, diminished reactive oxygen species (ROS) production, and oxidative stress. TUNEL staining confirmed that increased apoptosis in APAPtreated livers was significantly attenuated by MOTS-c, which are key contributors to hepatocyte death and liver injury. Mechanistic studies revealed that MOTS-c inhibited APAP-induced phosphorylation of MAPK pathway components, including ERK, JNK, and p38. The protective effects of MOTS-c on serum ALT and AST levels were abolished by co-treatment with inhibitors of ERK, JNK, and p38.

Discussion: This study reveals that the mitochondrial peptide MOTS-c can alleviate drug-induced liver injury by suppressing oxidative stress and inflammation via the MAPK pathway. This positions MOTS-c as a promising therapeutic candidate for treating APAP-induced liver injury.

Conclusion: This study demonstrates that administering MOTS-c effectively protects against APAP-induced liver injury in mice. The protective mechanism involves suppressing the damaging MAPK signaling pathway (ERK, JNK, p38), which in turn reduces oxidative stress, inflammation, and cell death.

查看原文本刊更多论文

MOTS-c通过MAPK信号通路保护对乙酰氨基酚诱导的肝损伤

目的：对乙酰氨基酚（APAP）诱导的肝损伤（AILI）是全球范围内急性肝衰竭的主要原因，但目前仍缺乏有效的治疗策略。MOTS-c是一种线粒体来源的肽，在非酒精性脂肪性肝炎（NASH）和乙型肝炎病毒（HBV）感染模型中显示出肝脏保护作用。本研究旨在探讨MOTS-c在AILI中的作用及其机制。方法：通过腹腔注射APAP （300 mg/kg）建立雄性C57BL/6小鼠AILI模型。通过行为测试、qPCR、western blotting、ELISA、免疫组织化学、免疫荧光和TUNEL染色评估MOTS-c的治疗潜力及其机制。结果：与对照组相比，apapp诱导的AILI小鼠血浆和肝组织中MOTS-c水平均显著降低。经腹腔注射MOTS-c可显著减弱apap诱导的AST和ALT水平升高、组织病理学肝损伤和其他肝损伤标志物。MOTS-c处理可抑制促炎因子（TNF-α、IL-1β、IL-6、COX-2）的释放和APAP诱导的巨噬细胞浸润。此外，MOTS-c处理显著恢复了GSH含量，减少了活性氧（ROS）的产生和氧化应激。TUNEL染色证实，MOTS-c显著减弱了apapp处理肝脏中增加的细胞凋亡，而细胞凋亡是导致肝细胞死亡和肝损伤的关键因素。机制研究表明，MOTS-c抑制apap诱导的MAPK通路组分的磷酸化，包括ERK、JNK和p38。MOTS-c与ERK、JNK和p38抑制剂联合治疗后，其对血清ALT和AST水平的保护作用被消除。讨论：本研究揭示线粒体肽MOTS-c可通过MAPK途径抑制氧化应激和炎症，从而减轻药物性肝损伤。这使得MOTS-c成为治疗apap诱导的肝损伤的有希望的治疗候选药物。结论：本研究表明给药MOTS-c对apap诱导的小鼠肝损伤有保护作用。这种保护机制包括抑制有害的MAPK信号通路（ERK、JNK、p38），从而减少氧化应激、炎症和细胞死亡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Protein and Peptide Letters 生物-生化与分子生物学

CiteScore

2.90

自引率

0.00%

发文量

审稿时长

2 months

期刊介绍： Protein & Peptide Letters publishes letters, original research papers, mini-reviews and guest edited issues in all important aspects of protein and peptide research, including structural studies, advances in recombinant expression, function, synthesis, enzymology, immunology, molecular modeling, and drug design. Manuscripts must have a significant element of novelty, timeliness and urgency that merit rapid publication. Reports of crystallization and preliminary structure determination of biologically important proteins are considered only if they include significant new approaches or deal with proteins of immediate importance, and preliminary structure determinations of biologically important proteins. Purely theoretical/review papers should provide new insight into the principles of protein/peptide structure and function. Manuscripts describing computational work should include some experimental data to provide confirmation of the results of calculations. Protein & Peptide Letters focuses on: Structure Studies Advances in Recombinant Expression Drug Design Chemical Synthesis Function Pharmacology Enzymology Conformational Analysis Immunology Biotechnology Protein Engineering Protein Folding Sequencing Molecular Recognition Purification and Analysis