{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:21Z","timestamp":1787029101769,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008402","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274043"],"award-info":[{"award-number":["82274043"]}],"id":[{"id":"10.13039\/501100008402","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008402","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U19A2010"],"award-info":[{"award-number":["U19A2010"]}],"id":[{"id":"10.13039\/501100008402","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008402","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021YFYZ0012-5"],"award-info":[{"award-number":["2021YFYZ0012-5"]}],"id":[{"id":"10.13039\/501100008402","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008402","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["ZYYCXTD-D-202209"],"award-info":[{"award-number":["ZYYCXTD-D-202209"]}],"id":[{"id":"10.13039\/501100008402","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sichuan Province Science and Technology Planning Project","award":["82274043"],"award-info":[{"award-number":["82274043"]}]},{"name":"Sichuan Province Science and Technology Planning Project","award":["U19A2010"],"award-info":[{"award-number":["U19A2010"]}]},{"name":"Sichuan Province Science and Technology Planning Project","award":["2021YFYZ0012-5"],"award-info":[{"award-number":["2021YFYZ0012-5"]}]},{"name":"Sichuan Province Science and Technology Planning Project","award":["ZYYCXTD-D-202209"],"award-info":[{"award-number":["ZYYCXTD-D-202209"]}]},{"name":"National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine","award":["82274043"],"award-info":[{"award-number":["82274043"]}]},{"name":"National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine","award":["U19A2010"],"award-info":[{"award-number":["U19A2010"]}]},{"name":"National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine","award":["2021YFYZ0012-5"],"award-info":[{"award-number":["2021YFYZ0012-5"]}]},{"name":"National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine","award":["ZYYCXTD-D-202209"],"award-info":[{"award-number":["ZYYCXTD-D-202209"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Liver fibrosis refers to a complex inflammatory response caused by multiple factors, which is a known cause of liver cirrhosis and even liver cancer. As a valuable medicine food homology herb, saffron has been widely used in the world. Saffron is commonly used in liver-related diseases and has rich therapeutic and health benefits. The therapeutic effect is satisfactory, but its mechanism is still unclear. In order to clarify these problems, we planned to determine the pharmacological effects and mechanisms of saffron extract in preventing and treating liver fibrosis through network pharmacology analysis combined with in vivo validation experiments. Through UPLC-Q-Exactive-MS analysis, a total of fifty-six nutrients and active ingredients were identified, and nine of them were screened to predict their therapeutic targets for liver fibrosis. Then, network pharmacology analysis was applied to identify 321 targets for saffron extract to alleviate liver fibrosis. Functional and pathway enrichment analysis showed that the putative targets of saffron for the treatment of hepatic fibrosis are mainly involved in the calcium signaling pathway, the HIF-1 signaling pathway, endocrine resistance, the PI3K\/Akt signaling pathway, lipid and atherosclerosis, and the cAMP signaling pathway. Based on the CCl4-induced liver fibrosis mice model, we experimentally confirmed that saffron extract can alleviate the severity and pathological changes during the progression of liver fibrosis. RT-PCR and Western blotting analysis confirmed that saffron treatment can prevent the CCl4-induced upregulation of HIF-1\u03b1, VEGFA, AKT, and PI3K, suggesting that saffron may regulate AKT\/HIF-1\u03b1\/VEGF and alleviate liver fibrosis.<\/jats:p>","DOI":"10.3390\/molecules28217238","type":"journal-article","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T11:39:04Z","timestamp":1698147544000},"page":"7238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Hepatoprotective Effect of Medicine Food Homology Flower Saffron against CCl4-Induced Liver Fibrosis in Mice via the Akt\/HIF-1\u03b1\/VEGF Signaling Pathway"],"prefix":"10.3390","volume":"28","author":[{"given":"Huajuan","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China"},{"name":"Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xulong","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China"},{"name":"Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Wang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei 230031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoxiang","family":"Ren","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China"},{"name":"Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China"},{"name":"Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Pei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China"},{"name":"Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,24]]},"reference":[{"key":"ref_1","first-page":"e202202905","article-title":"Liver disease in pediatric cystic fibrosis. A review of current knowledge","volume":"121","author":"Costaguta","year":"2023","journal-title":"Arch. Argent. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1177\/1535370219898141","article-title":"Mechanisms of liver fibrosis and its role in liver cancer","volume":"245","author":"Dhar","year":"2020","journal-title":"Exp. Biol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.3350\/cmh.2020.0187","article-title":"Anti-fibrotic treatments for chronic liver diseases: The present and the future","volume":"27","author":"Odagiri","year":"2021","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1055\/s-0035-1550055","article-title":"Antifibrotic Therapies in the Liver","volume":"35","author":"Mehal","year":"2015","journal-title":"Semin. Liver Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tan, Z., Sun, H.B., Xue, T.X., Gan, C.L., Liu, H.Y., Xie, Y.T., Yao, Y.Q., and Ye, T.H. (2021). Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.730176"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Vijayan, N., and Perumal, M.K. (2022). A critical review on anti-fibrotic phytochemicals targeting activated hepatic stellate cells. J. Food Biochem., 46.","DOI":"10.1111\/jfbc.14438"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5325431","DOI":"10.1155\/2022\/5325431","article-title":"Pathogenesis of Liver Fibrosis and Its TCM Therapeutic Perspectives","volume":"2022","author":"Nan","year":"2022","journal-title":"Evid.-Based Compl. Alt."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.1039\/D0FO03052J","article-title":"Essential oil from the raw and vinegar-processed Rhizoma Curcumae ameliorate CCl4-induced liver fibrosis: Integrating network pharmacology and molecular mechanism evaluation","volume":"12","author":"Chen","year":"2021","journal-title":"Food Funct."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"937484","DOI":"10.3389\/fphar.2022.937484","article-title":"Pien-Tze-Huang alleviates CCl4-induced liver fibrosis through the inhibition of HSC autophagy and the TGF-beta 1\/Smad2 pathway","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"945291","DOI":"10.3389\/fpls.2022.945291","article-title":"The menace of saffron adulteration: Low-cost rapid identification of fake look-alike saffron using Foldscope and machine learning technology","volume":"13","author":"Husaini","year":"2022","journal-title":"Front. Plant Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.fct.2013.11.016","article-title":"Bioactivity assessment and toxicity of crocin: A comprehensive review","volume":"64","author":"Alavizadeh","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"106237","DOI":"10.1016\/j.foodhyd.2020.106237","article-title":"Multifunctional halochromic packaging materials: Saffron petal anthocyanin loaded-chitosan nanofiber\/methyl cellulose matrices","volume":"111","author":"Tavassoli","year":"2021","journal-title":"Food Hydrocoll."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8214821","DOI":"10.1155\/2022\/8214821","article-title":"The Pharmacological Activities of Crocus sativus L.: A Review Based on the Mechanisms and Therapeutic Opportunities of its Phytoconstituents","volume":"2022","author":"Butnariu","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gupta, M., Ghufran, S.M., Kausar, T., Ali, R., Biswas, S., Nayeem, S.M., Ishrat, R., Ali, S., Ahmad, A., and Rather, I.A. (2022). Z-Guggulsterone Is a Potential Lead Molecule of Dawa-ul-Kurkum against Hepatocellular Carcinoma. Molecules, 27.","DOI":"10.3390\/molecules27165104"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/jcmm.16084","article-title":"Herbal formula LLKL ameliorates hyperglycaemia, modulates the gut microbiota and regulates the gut-liver axis in Zucker diabetic fatty rats","volume":"25","author":"Li","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1186\/s12906-016-1381-9","article-title":"Protective effects of saffron extract and crocin supplementation on fatty liver tissue of high-fat diet-induced obese rats","volume":"16","author":"Mashmoul","year":"2016","journal-title":"BMC Complement. Altern. Med."},{"key":"ref_17","unstructured":"Amin, A., Hamza, A.A., Daoud, S., Khazanehdari, K., Al Hrout, A., Baig, B., Chaiboonchoe, A., Adrian, T.E., Zaki, N., and Salehi-Ashtiani, K. (2016). Saffron\u2019s Bioactive Molecule Prevents Chemical Induced-Liver Cancer: A Pre-clinical Study. Mol. Biol. Cell, 27."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6315","DOI":"10.1080\/10408398.2021.1900059","article-title":"Does saffron supplementation have favorable effects on liver function indicators? A systematic review and meta-analysis of randomized controlled trials","volume":"62","author":"Mousavi","year":"2022","journal-title":"Crit. Rev. Food Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1159\/000515003","article-title":"The Effect of Saffron Consumption on Liver Function: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials","volume":"28","author":"Karimi","year":"2021","journal-title":"Complement. Med. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"681391","DOI":"10.3389\/fmed.2021.681391","article-title":"Exploring the Protective Effects and Mechanism of Crocetin from Saffron Against NAFLD by Network Pharmacology and Experimental Validation","volume":"8","author":"Xu","year":"2021","journal-title":"Front. Med."},{"key":"ref_21","first-page":"1","article-title":"TCM network pharmacology: A new trend towards combining computational, experimental and clinical approaches","volume":"19","author":"Wang","year":"2021","journal-title":"Chin. J. Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"218","DOI":"10.18433\/jpps32911","article-title":"Progress and Prospects of Research Ideas and Methods in the Network Pharmacology of Traditional Chinese Medicine","volume":"25","author":"Yuan","year":"2022","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/ddr.21214","article-title":"Network Pharmacology: A Rosetta Stone for Traditional Chinese Medicine","volume":"75","author":"Hao","year":"2014","journal-title":"Drug Develop. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"777500","DOI":"10.3389\/fphar.2021.777500","article-title":"Safranal Prevents Liver Cancer Through Inhibiting Oxidative Stress and Alleviating Inflammation","volume":"12","author":"Abdalla","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"635818","DOI":"10.3389\/fpubh.2021.635818","article-title":"Etiology Exploration of Non-alcoholic Fatty Liver Disease from Traditional Chinese Medicine Constitution Perspective: A Cross-Sectional Study","volume":"9","author":"Zhu","year":"2021","journal-title":"Front. Public Health"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"736","DOI":"10.3389\/fphar.2018.00736","article-title":"The Effects of Curcumae Longae Radix, Curcuma phaeocaulis Radix and Their Processed Products on Epo\/EpoR Pathway and CD62p","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1002\/hep.27376","article-title":"Liver Sinusoidal Endothelial Cells in Hepatic Fibrosis","volume":"61","author":"DeLeve","year":"2015","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhang, H.F., Gao, X., Wang, X., Chen, X., Huang, Y., Wang, L., and Xu, Z.W. (2021). The mechanisms of renin-angiotensin system in hepatocellular carcinoma: From the perspective of liver fibrosis, HCC cell proliferation, metastasis and angiogenesis, and corresponding protection measures. Biomed. Pharmacother., 141.","DOI":"10.1016\/j.biopha.2021.111868"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1248\/bpb.b15-00325","article-title":"Differential Roles of Angiogenesis in the Induction of Fibrogenesis and the Resolution of Fibrosis in Liver","volume":"38","author":"Park","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_30","first-page":"444","article-title":"Vascular endothelial growth factor (VEGF)\u2014Part 1: In physiology and pathophysiology","volume":"62","author":"Kajdaniuk","year":"2011","journal-title":"Endokrynol. Pol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biochi.2014.10.013","article-title":"Hypoxia-inducible factor-1alpha in hepatic fibrosis: A promising therapeutic target","volume":"108","author":"Zhan","year":"2015","journal-title":"Biochimie"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s00109-016-1408-1","article-title":"Hypoxia-inducible factors as molecular targets for liver diseases","volume":"94","author":"Ju","year":"2016","journal-title":"J. Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Bakshi, H.A., Quinn, G.A., Nasef, M.M., Mishra, V., Aljabali, A.A.A., El-Tanani, M., Serrano-Aroca, A., Da Silva, M.W., McCarron, P.A., and Tambuwala, M.M. (2022). Crocin Inhibits Angiogenesis and Metastasis in Colon Cancer via TNF-alpha\/NF-kB\/VEGF Pathways. Cells, 11.","DOI":"10.3390\/cells11091502"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"675359","DOI":"10.3389\/fphar.2021.675359","article-title":"Crocetin and Its Glycoside Crocin, Two Bioactive Constituents from Crocus sativus L. (Saffron), Differentially Inhibit Angiogenesis by Inhibiting Endothelial Cytoskeleton Organization and Cell Migration Through VEGFR2\/SRC\/FAK and VEGFR2\/MEK\/ERK Signaling Pathways","volume":"12","author":"Zhao","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1097\/MCA.0000000000001142","article-title":"Mechanistic insights on the effect of crocin, an active ingredient of saffron, on atherosclerosis in apolipoprotein E knockout mice","volume":"33","author":"Makaritsis","year":"2022","journal-title":"Coron. Artery Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17876","DOI":"10.1002\/jcp.28418","article-title":"Crocin inhibits the migration, invasion, and epithelial-mesenchymal transition of gastric cancer cells via miR-320\/KLF5\/HIF-1 alpha signaling","volume":"234","author":"Zhou","year":"2019","journal-title":"J. Cell Physiol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/21\/7238\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:10:43Z","timestamp":1760130643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/21\/7238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,24]]},"references-count":36,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["molecules28217238"],"URL":"https:\/\/doi.org\/10.3390\/molecules28217238","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,24]]}}}