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Mechanisms underlying FXR-ER stress interactions in combating NAFLD remain obscure, and few phytochemicals improve NAFLD via this pathway. FXR activation induces SERCA2 transcription, repressing ER stress by modulating eIF2a dephosphorylation. Atractylenolide II is identified as an FXR agonist activating SERCA2, suppressing lipid and ER stress in vitro and attenuating fatty liver and insulin resistance in vivo through the hepatic FXR-SERCA2-eIF2a axis.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/unlocking-the-potential-of-atractylenolide-ii-mitigating-non-alcoholic-fatty-liver-disease-through-farnesoid-x-receptor-endoplasmic-reticulum-stress-interplay/432472/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/unlocking-the-potential-of-atractylenolide-ii-mitigating-non-alcoholic-fatty-liver-disease-through-farnesoid-x-receptor-endoplasmic-reticulum-stress-interplay/432472.png","ImageObject",300,407,{"name":92,"@type":93},"Franzy","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"How does FXR activation alleviate NAFLD-related ER stress?","Question",{"text":113,"@type":114},"FXR activation directly induces SERCA2 transcription, which acts as an ER stress repressor. This leads to eIF2a dephosphorylation in hepatocytes and consequently alleviates ER stress.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What role does atractylenolide II play in the FXR-SERCA2 pathway?",{"text":118,"@type":114},"Atractylenolide II is identified as a novel FXR agonist that activates SERCA2. It suppresses lipid accumulation and ER stress in palmitic acid-induced hepatocytes and improves hepatic insulin signaling in mice.",{"name":120,"@type":111,"acceptedAnswer":121},"What experimental evidence supports SERCA2 as a key mediator?",{"text":122,"@type":114},"The conclusion is supported by Serca2 knockdown both in vivo and in vitro, as well as FXR silencing in hepatocytes, demonstrating the involvement of the hepatic FXR-SERCA2-eIF2a axis.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},432472,1791117527,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},2336478945519,"https://ap-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Journal of Pharmaceutical Analysis 15 (2025) 101318  \nContents lists available at ScienceDirect  \nJournal of Pharmaceutical Analysis  \njournal [homepage:](homepage: www. elsevier. com/locate/jpa)[ www. elsevier. com/locate/jpa](homepage: www. elsevier. com/locate/jpa)  \n| Original article |  |  |\n| --- | --- | --- |\n| Unlocking the potential of atractylenolide II: Mitigating non-alcoholic fatty liver disease through farnesoid X receptor-endoplasmic reticulum stress interplay |  | |\n| Ming Gu a, 1, *, Zhiwei Chen a, 1, Yujun Chen a, Yiping Li a, Hongqing Wang b, Ya-ru Feng b, Peiyong Zheng a, **, Cheng Huang b, ***\u003Cbr>a Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China b School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China |  |  |\n| a r t i c l e i n f o | a b s t r a c t\u003Cbr>Evidences indicate that farnesoid X receptor (FXR) activation mitigates non-alcoholic fatty liver disease (NAFLD) by reducing endoplasmic reticulum (ER) stress. However, the mechanisms underlying FXR-ER stress interactions in combating NAFLD remain obscure. Moreover, few phytochemicals have been noted to improve NAFLD through this pathway. Here, we found that FXR activation directly induces the transcription of sarco/endoplasmic reticulum Ca2þ ATPase 2 (SERCA2), which acts as an ER stress repressor. This process leads to the dephosphorylation of the eukaryotic translation initiation factor 2 subunit a (eIF2a) within hepatocytes, consequently alleviating ER stress. Furthermore, through drug binding assays, luciferase reporter gene testing, gene expression analysis and biochemical evaluation, weidentified the phytochemical atractylenolide II (AT-II) as a novel FXR agonist that effectively triggers SERCA2 activation. Our results showed AT-II effectively supresses accumulation of lipids and ER stress in palmitic acid-induced hepatocytes. In in vivo experiments, we demonstrated that AT-II attenuates fatty liver in diet- or chemical-induced NAFLD mouse models. Additionally, we showed that AT-II corrects diet-induced obesity, serum dyslipidemia, metabolic complications, and insulin resistance. Mechanistically, AT-II reduces ER stress, lipogenesis and inflammation and improves hepatic insulin signaling through stimulation of the hepatic FXR-SERCA2-eIF2a axis in mice. This conclusion was further reinforced by Serca2 knockdown both in vivo and in vitro, as well as FXR silencing in hepatocytes. Our findings provide new insights into the FXR-ER stress interplay in the control of NAFLD and suggest the potential of AT-II as an FXR agonist for the treatment of NAFLD through SERCA2 activation.\u003Cbr>© 2025 The Authors. Published by Elsevier B.V. on behalf of Xi’an Jiaotong University. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/) ). |  |\n| Article history:\u003Cbr>Received 11 November 2024\u003Cbr>Received in revised form\u003Cbr>7 April 2025\u003Cbr>Accepted 16 April 2025\u003Cbr>Available online 21 April 2025 |  |  |\n| Keywords:\u003Cbr>Endoplasmic reticulum stress\u003Cbr>Farnesoid X receptor\u003Cbr>Sarco/endoplasmic reticulum Ca2þ ATPase 2 Non-alcoholic fatty liver disease atractylenolide II |  |  |\n\n1. Introduction  \nNon-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is a widespread chronic liver condition that affects more than one-  \nthird of the global population [1]. NAFLD can progress to nonalcoholic steatohepatitis (NASH) and liver fibrosis, which may lead to liver cancer and cirrhosis [2]. There is a significant association between NAFLD and conditions such as type 2 diabetes mellitus (T2DM), obesity, and hyperlipidemia [3]. However, given  \nPeer review under responsibility of Xi'an Jiaotong University.  \n* Corresponding author.  \n** Corresponding author.  \n*** Corresponding author.  \nE-mail [addresses:](addresses: ","cbCaisgGlDCWOgok","https://ap.wps.com/l/cbCaisgGlDCWOgok","pdf",8169654,"English","# Abstract\n# Keywords\n# Introduction","[{\"question\":\"How does FXR activation alleviate NAFLD-related ER stress?\",\"answer\":\"FXR activation directly induces SERCA2 transcription, which acts as an ER stress repressor. This leads to eIF2a dephosphorylation in hepatocytes and consequently alleviates ER stress.\"},{\"question\":\"What role does atractylenolide II play in the FXR-SERCA2 pathway?\",\"answer\":\"Atractylenolide II is identified as a novel FXR agonist that activates SERCA2. It suppresses lipid accumulation and ER stress in palmitic acid-induced hepatocytes and improves hepatic insulin signaling in mice.\"},{\"question\":\"What experimental evidence supports SERCA2 as a key mediator?\",\"answer\":\"The conclusion is supported by Serca2 knockdown both in vivo and in vitro, as well as FXR silencing in hepatocytes, demonstrating the involvement of the hepatic FXR-SERCA2-eIF2a axis.\"}]","Unlocking the potential of atractylenolide II - Mitigating non-alcoholic fatty liver disease through farnesoid X receptor-endoplasmic reticulum stress interplay | PDF",1790659821,48]