{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T21:54:27Z","timestamp":1789768467330,"version":"4.0.1"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2023-I2M-2-006"],"award-info":[{"award-number":["2023-I2M-2-006"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2024-I2M-ZH-012"],"award-info":[{"award-number":["2024-I2M-ZH-012"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2025-I2M-KJ-018"],"award-info":[{"award-number":["2025-I2M-KJ-018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver fibrosis, a progressive condition with limited pharmacotherapies, poses a global health challenge. Scutellarin (SCU), a flavonoid derived from Erigeron breviscapus, has demonstrated anti-fibrotic activity and modulates gut microbiota. Emerging evidence suggests that SCU may also influence the hepatic microbiome. However, its clinical utility is constrained by poor water solubility and low oral bioavailability. Here, we developed an SCU-loaded nanoemulsion (SCE) to enhance solubility and liver-targeted delivery. In vitro, SCE increased SCU uptake in hepatic stellate cells (HSCs) and significantly inhibited TGF-\u03b21-induced fibrogenesis. In a bile duct ligation (BDL) mouse model, oral administration of SCE improved hepatic SCU accumulation and produced superior anti-fibrotic efficacy. SCE treatment attenuated fibrosis and collagen deposition in the liver and improved liver function markers. Mechanistic investigations using 16S rRNA sequencing revealed that SCU treatment was associated with beneficial microbiota changes, although its main therapeutic effects were achieved through enhanced hepatic targeting. Notably, the SCE formulation was well-tolerated, showing no significant toxicity in vitro or in vivo. In conclusion, the SCU-loaded nanoemulsion achieved enhanced hepatic delivery of SCU and exerted potent anti-fibrotic effects via multiple mechanisms, including direct suppression of fibrogenesis and ancillary modulation of the gut\u2013liver microbiome, offering a promising therapeutic strategy for liver fibrosis.<\/jats:p>","DOI":"10.3390\/ijms26199746","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T10:48:07Z","timestamp":1759834087000},"page":"9746","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Liver-Targeted Scutellarin Nanoemulsion Alleviates Fibrosis with Ancillary Modulation of the Gut\u2013Liver Microbiota"],"prefix":"10.3390","volume":"26","author":[{"given":"Haoyang","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Niu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyu","family":"Niu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Lei","sequence":"additional","affiliation":[{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanyong","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangning Campus, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8585-6286","authenticated-orcid":false,"given":"Guiling","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7186-5251","authenticated-orcid":false,"given":"Lulu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/j.cmet.2022.09.017","article-title":"Gut-liver axis: Pathophysiological concepts and clinical implications","volume":"34","author":"Tilg","year":"2022","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Miao, Z., Lai, Y., Zhao, Y., Chen, L., Zhou, J., Li, C., and Wang, Y. (2021). Protective Property of Scutellarin Against Liver Injury Induced by Carbon Tetrachloride in Mice. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.710692"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1039\/D2FO02523J","article-title":"Thyme (Thymus vulgaris L.) polyphenols ameliorate DSS-induced ulcerative colitis of mice by mitigating intestinal barrier damage, regulating gut microbiota, and suppressing TLR4\/NF-\u03baB-NLRP3 inflammasome pathways","volume":"14","author":"Zhou","year":"2023","journal-title":"Food Funct."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106055","DOI":"10.1016\/j.phrs.2021.106055","article-title":"Polypharmacology: The science of multi-targeting molecules","volume":"176","author":"Kabir","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23608","DOI":"10.1021\/acsnano.3c06626","article-title":"Hepatic Stellate Cell- and Liver Microbiome-Specific Delivery System for Dihydrotanshinone I to Ameliorate Liver Fibrosis","volume":"17","author":"Niu","year":"2023","journal-title":"ACS Nano"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1007\/s11033-021-07026-0","article-title":"Scutellarein protects against cardiac hypertrophy via suppressing TRAF2\/NF-\u03baB signaling pathway","volume":"49","author":"Shi","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wu, H., and Jia, L. (2019). Scutellarin attenuates hypoxia\/reoxygenation injury in hepatocytes by inhibiting apoptosis and oxidative stress through regulating Keap1\/Nrf2\/ARE signaling. Biosci. Rep., 39.","DOI":"10.1042\/BSR20192501"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1002\/ar.24175","article-title":"Role of Scutellarin in Ameliorating Lung Injury in a Rat Model of Bilateral Hind Limb Ischemia-Reperfusion","volume":"302","author":"Ibrahim","year":"2019","journal-title":"Anat. Rec."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.pharmthera.2018.05.006","article-title":"Clinical benefits and pharmacology of scutellarin: A comprehensive review","volume":"190","author":"Wang","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3996","DOI":"10.2174\/1381612827666210705160130","article-title":"Mechanistic Aspects of Medicinal Plants and Secondary Metabolites against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)","volume":"27","author":"Malekmohammad","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"ref_14","first-page":"315","article-title":"Protective effects of Erigeron breviscapus Hand.- Mazz. (EBHM) extract in retinal neurodegeneration models","volume":"24","author":"Zhu","year":"2018","journal-title":"Mol. Vis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chen, S., Li, R., Chen, Y., Chou, C.K., Zhang, Z., Yang, Y., Liao, P., Wang, Q., and Chen, X. (2022). Scutellarin enhances anti-tumor immune responses by reducing TNFR2-expressing CD4(+)Foxp3(+) regulatory T cells. Biomed. Pharmacother., 151.","DOI":"10.1016\/j.biopha.2022.113187"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1111\/j.1476-5381.2010.01070.x","article-title":"Scutellarin alleviates interstitial fibrosis and cardiac dysfunction of infarct rats by inhibiting TGF\u03b21 expression and activation of p38-MAPK and ERK1\/2","volume":"162","author":"Pan","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/s41419-020-03178-2","article-title":"Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-\u03baB\/NLRP3-mediated epithelial-mesenchymal transition and inflammation","volume":"11","author":"Peng","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Shi, Y., Liu, Y., Wang, S., Huang, J., Luo, Z., Jiang, M., Lu, Y., Lin, Q., Liu, H., and Cheng, N. (2022). Endoplasmic reticulum-targeted inhibition of CYP2E1 with vitamin E nanoemulsions alleviates hepatocyte oxidative stress and reverses alcoholic liver disease. Biomaterials, 288.","DOI":"10.1016\/j.biomaterials.2022.121720"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6213","DOI":"10.1021\/acs.jafc.3c07902","article-title":"Novel Human Milk Fat Substitutes Based on Medium- and Long-Chain Triacylglycerol Regulate Thermogenesis, Lipid Metabolism, and Gut Microbiota Diversity in C57BL\/6J Mice","volume":"72","author":"Yuan","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Huang, J.H., Wang, J., Chai, X.Q., Li, Z.C., Jiang, Y.H., Li, J., Liu, X., Fan, J., Cai, J.B., and Liu, F. (2022). The Intratumoral Bacterial Metataxonomic Signature of Hepatocellular Carcinoma. Microbiol. Spectr., 10.","DOI":"10.1128\/spectrum.00983-22"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"169642","DOI":"10.1016\/j.scitotenv.2023.169642","article-title":"Gut microbiota disorders aggravate terbuthylazine-induced mitochondrial quality control disturbance and PANoptosis in chicken hepatocyte through gut-liver axis","volume":"913","author":"Li","year":"2024","journal-title":"Sci. Total. Environ."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/s41591-019-0504-5","article-title":"Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice","volume":"25","author":"Mayoral","year":"2019","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"810","DOI":"10.3748\/wjg.v23.i5.810","article-title":"Gut microbial diversity analysis using Illumina sequencing for functional dyspepsia with liver depression-spleen deficiency syndrome and the interventional Xiaoyaosan in a rat model","volume":"23","author":"Qiu","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liu, X., Ma, Q., Feng, Y., Wang, F., Wang, W., Wang, J., and Sun, J. (2024). Potato resistant starch improves type 2 diabetes by regulating inflammation, glucose and lipid metabolism and intestinal microbial environment. Int. J. Biol. Macromol., 281.","DOI":"10.1016\/j.ijbiomac.2024.136389"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1039\/D3FO05459D","article-title":"Theabrownin from Fu Brick tea ameliorates high-fat induced insulin resistance, hepatic steatosis, and inflammation in mice by altering the composition and metabolites of gut microbiota","volume":"15","author":"Lu","year":"2024","journal-title":"Food Funct."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pan, X., Kaminga, A.C., Liu, A., Wen, S.W., Luo, M., and Luo, J. (2021). Gut Microbiota, Glucose, Lipid, and Water-Electrolyte Metabolism in Children With Nonalcoholic Fatty Liver Disease. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.683743"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/hep.28696","article-title":"Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice","volume":"64","author":"Kang","year":"2016","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1136\/gutjnl-2019-319664","article-title":"Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites","volume":"70","author":"Zhang","year":"2021","journal-title":"Gut"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1930874","DOI":"10.1080\/19490976.2021.1930874","article-title":"Desulfovibrio vulgaris, a potent acetic acid-producing bacterium, attenuates nonalcoholic fatty liver disease in mice","volume":"13","author":"Hong","year":"2021","journal-title":"Gut Microbes"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yan, F., Zhang, Q., Shi, K., Zhang, Y., Zhu, B., Bi, Y., and Wang, X. (2023). Gut microbiota dysbiosis with hepatitis B virus liver disease and association with immune response. Front. Cell. Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1152987"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/hep.30036","article-title":"Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease","volume":"69","author":"Ponziani","year":"2019","journal-title":"Hepatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/hep.28356","article-title":"The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota","volume":"63","author":"Boursier","year":"2016","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7692","DOI":"10.1039\/D3FO01684F","article-title":"Nobiletin protects against ferroptosis to alleviate sepsis-associated acute liver injury by modulating the gut microbiota","volume":"14","author":"Huang","year":"2023","journal-title":"Food Funct."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7145","DOI":"10.1039\/D1FO00218J","article-title":"The beneficial effects of Lactobacillus brevis FZU0713-fermented Laminaria japonica on lipid metabolism and intestinal microbiota in hyperlipidemic rats fed with a high-fat diet","volume":"12","author":"Zhang","year":"2021","journal-title":"Food Funct."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Carter, J.K., Bhattacharya, D., Borgerding, J.N., Fiel, M.I., Faith, J.J., and Friedman, S.L. (2021). Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0244763"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhou, D., Zhang, J., Xiao, C., Mo, C., and Ding, B.S. (2022). Trimethylamine-N-oxide (TMAO) mediates the crosstalk between the gut microbiota and hepatic vascular niche to alleviate liver fibrosis in nonalcoholic steatohepatitis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.964477"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1053\/j.gastro.2020.01.031","article-title":"Synbiotics Alter Fecal Microbiomes, But Not Liver Fat or Fibrosis, in a Randomized Trial of Patients With Nonalcoholic Fatty Liver Disease","volume":"158","author":"Scorletti","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of hepatic fibrogenesis","volume":"134","author":"Friedman","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhou, H., Wan, J., Wu, L., Yi, T., Liu, W., Xu, H., and Yang, X. (2013). A new strategy for enhancing the oral bioavailability of drugs with poor water-solubility and low liposolubility based on phospholipid complex and supersaturated SEDDS. PLoS ONE, 8, Correction in PLoS ONE 2014, 9, e91605.","DOI":"10.1371\/journal.pone.0091605"},{"key":"ref_40","first-page":"79","article-title":"Lipid-based nanoparticle technologies for liver targeting","volume":"154\u2013155","author":"Pauli","year":"2020","journal-title":"Adv. Drug. Deliv. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"S460","DOI":"10.1177\/09603271211045948","article-title":"Scutellarin alleviates type 2 diabetes (HFD\/low dose STZ)-induced cardiac injury through modulation of oxidative stress, inflammation, apoptosis and fibrosis in mice","volume":"40","author":"Huo","year":"2021","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Huang, B., Han, R., Tan, H., Zhu, W., Li, Y., Jiang, F., Xie, C., Ren, Z., and Shi, R. (2024). Scutellarin ameliorates diabetic nephropathy via TGF-\u03b21 signaling pathway. Nat. Prod. Bioprospect, 14.","DOI":"10.1007\/s13659-024-00446-y"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"S463","DOI":"10.1172\/JCI151725","article-title":"Intrahepatic microbes govern liver immunity by programming NKT cells","volume":"132","author":"Leinwand","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100299","DOI":"10.1016\/j.jhepr.2021.100299","article-title":"Hepatic microbiome in healthy lean and obese humans","volume":"3","author":"Suppli","year":"2021","journal-title":"JHEP Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9746\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T04:35:14Z","timestamp":1760070914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9746"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":44,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199746"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199746","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]}}}