ROS-Mediated Unfolded Protein Response Activation Drives Hepatocyte Apoptosis in Mesaconitine-Induced Liver Injury
Mesaconitine (MA), a predominant diterpenoid alkaloid isolated from Aconitum species, exhibits notable pharmacological properties but is simultaneously associated with significant toxicological concerns, with its hepatotoxic mechanisms remaining largely unelucidated. In this study, zebrafish embryos...
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2025-02-01
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| author | Jin Tian Yubin Zhuang Yinuo Liu Yihong Zheng Xuyang Liu Shiyu Lin Chenhua Zheng Zekai Wu |
| author_facet | Jin Tian Yubin Zhuang Yinuo Liu Yihong Zheng Xuyang Liu Shiyu Lin Chenhua Zheng Zekai Wu |
| author_sort | Jin Tian |
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| description | Mesaconitine (MA), a predominant diterpenoid alkaloid isolated from Aconitum species, exhibits notable pharmacological properties but is simultaneously associated with significant toxicological concerns, with its hepatotoxic mechanisms remaining largely unelucidated. In this study, zebrafish embryos were systematically exposed to MA to investigate its effects on hepatic development and function. Comprehensive analyses of liver morphology, inflammatory response, oxidative stress, and apoptotic pathways were conducted. MA induced dose-dependent hepatotoxicity, manifesting in a significant reduction in liver size and a marked downregulation of liver-specific genes, including <i>tfa</i>, <i>cp</i>, <i>hhex</i>, and <i>fabp10a</i>. The presence of oxidative stress was substantiated by elevated reactive oxygen species (ROS) levels, while hepatic inflammation was characterized by enhanced neutrophil infiltration and the upregulation of proinflammatory mediators, particularly <i>il1b</i> and <i>tnfa</i>. A global transcriptome analysis revealed the substantial upregulation of unfolded protein response (UPR)-associated genes, notably <i>hsp90b1</i>, <i>hspa5</i>, and <i>hspb9</i>, indicating that MA-induced oxidative stress triggered endoplasmic reticulum (ER) stress and subsequent UPR activation. Prolonged ER stress ultimately resulted in hepatocyte apoptosis, as demonstrated by the increased expression of the pro-apoptotic genes <i>casp3a</i>, <i>casp3b</i>, and <i>baxa</i>. These findings elucidate the molecular mechanisms underlying MA-induced hepatotoxicity and identify potential therapeutic targets for preventing and treating liver injury associated with Aconitum alkaloid exposure. |
| format | Article |
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| spelling | doaj-art-81f170e9ecb845dd86945b89aa4fe5f52025-08-20T02:43:04ZengMDPI AGToxics2305-63042025-02-0113315510.3390/toxics13030155ROS-Mediated Unfolded Protein Response Activation Drives Hepatocyte Apoptosis in Mesaconitine-Induced Liver InjuryJin Tian0Yubin Zhuang1Yinuo Liu2Yihong Zheng3Xuyang Liu4Shiyu Lin5Chenhua Zheng6Zekai Wu7Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaLaboratory Animal Center, Fujian Medical University, Fuzhou 350122, ChinaKey Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaKey Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaKey Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaKey Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaExperiment Teaching Center of Basic Medical Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaKey Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, ChinaMesaconitine (MA), a predominant diterpenoid alkaloid isolated from Aconitum species, exhibits notable pharmacological properties but is simultaneously associated with significant toxicological concerns, with its hepatotoxic mechanisms remaining largely unelucidated. In this study, zebrafish embryos were systematically exposed to MA to investigate its effects on hepatic development and function. Comprehensive analyses of liver morphology, inflammatory response, oxidative stress, and apoptotic pathways were conducted. MA induced dose-dependent hepatotoxicity, manifesting in a significant reduction in liver size and a marked downregulation of liver-specific genes, including <i>tfa</i>, <i>cp</i>, <i>hhex</i>, and <i>fabp10a</i>. The presence of oxidative stress was substantiated by elevated reactive oxygen species (ROS) levels, while hepatic inflammation was characterized by enhanced neutrophil infiltration and the upregulation of proinflammatory mediators, particularly <i>il1b</i> and <i>tnfa</i>. A global transcriptome analysis revealed the substantial upregulation of unfolded protein response (UPR)-associated genes, notably <i>hsp90b1</i>, <i>hspa5</i>, and <i>hspb9</i>, indicating that MA-induced oxidative stress triggered endoplasmic reticulum (ER) stress and subsequent UPR activation. Prolonged ER stress ultimately resulted in hepatocyte apoptosis, as demonstrated by the increased expression of the pro-apoptotic genes <i>casp3a</i>, <i>casp3b</i>, and <i>baxa</i>. These findings elucidate the molecular mechanisms underlying MA-induced hepatotoxicity and identify potential therapeutic targets for preventing and treating liver injury associated with Aconitum alkaloid exposure.https://www.mdpi.com/2305-6304/13/3/155mesaconitine (MA)hepatotoxicityinflammationoxidative stressapoptosisunfolded protein response (UPR) |
| spellingShingle | Jin Tian Yubin Zhuang Yinuo Liu Yihong Zheng Xuyang Liu Shiyu Lin Chenhua Zheng Zekai Wu ROS-Mediated Unfolded Protein Response Activation Drives Hepatocyte Apoptosis in Mesaconitine-Induced Liver Injury Toxics mesaconitine (MA) hepatotoxicity inflammation oxidative stress apoptosis unfolded protein response (UPR) |
| title | ROS-Mediated Unfolded Protein Response Activation Drives Hepatocyte Apoptosis in Mesaconitine-Induced Liver Injury |
| title_full | ROS-Mediated Unfolded Protein Response Activation Drives Hepatocyte Apoptosis in Mesaconitine-Induced Liver Injury |
| title_fullStr | ROS-Mediated Unfolded Protein Response Activation Drives Hepatocyte Apoptosis in Mesaconitine-Induced Liver Injury |
| title_full_unstemmed | ROS-Mediated Unfolded Protein Response Activation Drives Hepatocyte Apoptosis in Mesaconitine-Induced Liver Injury |
| title_short | ROS-Mediated Unfolded Protein Response Activation Drives Hepatocyte Apoptosis in Mesaconitine-Induced Liver Injury |
| title_sort | ros mediated unfolded protein response activation drives hepatocyte apoptosis in mesaconitine induced liver injury |
| topic | mesaconitine (MA) hepatotoxicity inflammation oxidative stress apoptosis unfolded protein response (UPR) |
| url | https://www.mdpi.com/2305-6304/13/3/155 |
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