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Although 3-Indolepropionic acid (IPA) is regarded as a clinically valuable gut metabolite for the treatment of certain chronic diseases, the effects of oral administration of IPA on hepatic fibrosis in different animal models have been conflicting. While some mechanisms have been proposed to explain these contradictory effects, the direct impact of IPA on hepatic fibrosis remains unclear. In this study, we found that IPA could directly activate LX-2 human hepatic stellate cells in vitro. IPA upregulated the expression of fibrogenic marker genes and promoted the features associated with HSCs activation, including proliferation and contractility. IPA also increased reactive oxygen species (ROS) in mitochondria and the expression of inflammation-related genes in LX-2 cells. However, when a ROS-blocking agent was used, these effects were reduced. p38 and JNK, the downstream signaling cascades of ROS, were found to be required for the activation of LX-2 induced by IPA. These findings suggest that IPA can directly activate hepatic stellate cells through ROS-induced JNK and p38 signaling pathways.<\/jats:p>","DOI":"10.3390\/biom13101464","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T08:24:44Z","timestamp":1695889484000},"page":"1464","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Gut Microbiota Metabolite 3-Indolepropionic Acid Directly Activates Hepatic Stellate Cells by ROS\/JNK\/p38 Signaling Pathways"],"prefix":"10.3390","volume":"13","author":[{"given":"Xiaoyan","family":"Yuan","sequence":"first","affiliation":[{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junting","family":"Yang","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"School of Life and Pharmaceutical Sciences, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mam.2018.09.002","article-title":"Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues","volume":"65","author":"Parola","year":"2019","journal-title":"Mol. 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