{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:52:38Z","timestamp":1790689958431,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T00:00:00Z","timestamp":1742428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ganpo Talent Support Program-Leading Academic and Technical Personnel in Major Disciplines","award":["20232BCJ23104"],"award-info":[{"award-number":["20232BCJ23104"]}]},{"name":"Ganpo Talent Support Program-Leading Academic and Technical Personnel in Major Disciplines","award":["22074141"],"award-info":[{"award-number":["22074141"]}]},{"name":"National Natural Science Foundation of China","award":["20232BCJ23104"],"award-info":[{"award-number":["20232BCJ23104"]}]},{"name":"National Natural Science Foundation of China","award":["22074141"],"award-info":[{"award-number":["22074141"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Danshen, a well-known traditional Chinese medicine (TCM), has gained increasing attention for its protective effects on nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying these effects remain to be elucidated. Niemann-Pick C1-like 1 (NPC1L1), a key transporter mediating intestinal cholesterol absorption, has emerged as a critical target for NAFLD treatment. This study aimed to screen for NPC1L1 inhibitors from Danshen and investigate their therapeutic effects on NAFLD. We established a high-throughput screening platform using stable Caco2 cell lines expressing human NPC1L1 (hL1-Caco2) and discovered that tanshinones (Tans), the liposoluble components of Danshen, inhibited NPC1L1-mediated cholesterol absorption in hL1-Caco2 cells. Additionally, Tans treatment reduced hepatic steatosis in high-fat diet (HFD)-fed mice. To identify the active compounds in Tans, activity-oriented separation was performed by integrating the high-throughput screening platform and two-dimensional chromatographic techniques. Ultimately, cryptotanshinone (CTS) was identified as a novel NPC1L1 inhibitor and significantly decreased hepatic steatosis in HFD-fed mice. Molecular docking and dynamics simulation showed that CTS stably bound with NPC1L1, where TRP383 acted as the key amino acid. Taken together, this study demonstrates, for the first time, that CTS, a liposoluble compound from Danshen, is a novel NPC1L1 inhibitor. Our findings suggest that the inhibitory effect of CTS against NPC1L1-mediated intestinal cholesterol absorption may be a potential mechanism, contributing to its alleviation of NAFLD in mice.<\/jats:p>","DOI":"10.3390\/ijms26062793","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T05:03:59Z","timestamp":1742447039000},"page":"2793","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of a Novel NPC1L1 Inhibitor from Danshen and Its Role in Nonalcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Donghai","family":"Xia","sequence":"first","affiliation":[{"name":"Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7172-7502","authenticated-orcid":false,"given":"Xuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China"},{"name":"Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Xie","sequence":"additional","affiliation":[{"name":"Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China"},{"name":"Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongping","family":"Yu","sequence":"additional","affiliation":[{"name":"Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaowa","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China"},{"name":"Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianlong","family":"Ye","sequence":"additional","affiliation":[{"name":"Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenglong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimou","family":"Guo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China"},{"name":"Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmiao","family":"Liang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China"},{"name":"Ganjiang Chinese Medicine Innovation Center, Nanchang 330000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/S0140-6736(20)32511-3","article-title":"Non-alcoholic fatty liver disease","volume":"397","author":"Powell","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.jhep.2021.11.009","article-title":"A new perspective on NAFLD: Focusing on lipid droplets","volume":"76","author":"Scorletti","year":"2022","journal-title":"J. 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