{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:35:57Z","timestamp":1787567757787,"version":"build-2736575974"},"reference-count":61,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32260132"],"award-info":[{"award-number":["32260132"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32260132"],"award-info":[{"award-number":["32260132"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Yunnan Provincial University Serving Key Industry Science and Technology Special Project","award":["FWCY-ZD2024009"],"award-info":[{"award-number":["FWCY-ZD2024009"]}]},{"DOI":"10.13039\/501100007846","name":"Joint Special Project for Basic Research of Local Universities in Yunnan Province","doi-asserted-by":"publisher","award":["202301BA070001-105"],"award-info":[{"award-number":["202301BA070001-105"]}],"id":[{"id":"10.13039\/501100007846","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007846","name":"Joint Special Project for Basic Research of Local Universities in Yunnan Province","doi-asserted-by":"publisher","award":["202101BA070001-143"],"award-info":[{"award-number":["202101BA070001-143"]}],"id":[{"id":"10.13039\/501100007846","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Yunnan International Joint Laboratory with South and Southeast Asia for the Integrated Development of Animal- Derived Anti-Thrombosis Chinese Medicine","award":["202503AP140025"],"award-info":[{"award-number":["202503AP140025"]}]},{"name":"Frontier Research Team of Kunming University 2023"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Hyperlipidemia (HL) is a major metabolic disorder and a critical risk factor for cardiovascular diseases, closely associated with oxidative stress, inflammation, and disrupted cholesterol homeostasis. Freeze-dried Poecilobdella manillensis powder (FDPMP), a traditional medicinal product, has shown therapeutic potential against hyperlipidemia; however, its underlying mechanisms remain largely unclear. In this study, HL was induced in ApoE\u2212\/\u2212 mice by feeding a high-fat diet (HFD) for eight weeks, during which FDPMP or simvastatin (positive control) was orally administered daily. Concurrently, an in vitro foam cell model was established by exposing RAW264.7 macrophages to oxidized low-density lipoprotein (ox-LDL, 80 \u03bcg\/mL) for 24 h, with FDPMP pretreatment applied 30 min prior to ox-LDL stimulation. Following intervention, serum lipid profiles, hepatic oxidative stress markers, histopathological changes, and cholesterol metabolism-related gene and protein expression were systematically evaluated. FDPMP administration significantly improved serum lipid profiles by reducing triglycerides, total cholesterol, and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol levels. Additionally, FDPMP alleviated histopathological damage in the liver, kidney, and heart, enhanced antioxidant enzyme activities, and attenuated oxidative stress. Untargeted metabolomic analysis revealed that FDPMP markedly modulated key metabolic pathways, including choline metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism. Mechanistically, FDPMP restored cholesterol homeostasis through dual regulation of cholesterol metabolism, characterized by upregulation of cholesterol 7\u03b1-hydroxylase (CYP7A1) to promote bile acid-mediated cholesterol excretion, alongside downregulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and synthase (HMGCS1) to inhibit cholesterol biosynthesis. In vitro, FDPMP effectively suppressed ox-LDL-induced foam cell formation, reduced intracellular lipid accumulation, and mitigated oxidative stress in macrophages. Collectively, these findings demonstrate that FDPMP ameliorates hyperlipidemia through coordinated regulation of cholesterol synthesis and excretion, coupled with systemic metabolic reprogramming and antioxidative effects. This study provides mechanistic insights supporting FDPMP as a promising natural therapeutic candidate for hyperlipidemia and related metabolic disorders.<\/jats:p>","DOI":"10.3390\/biom16081168","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T13:46:16Z","timestamp":1786455976000},"page":"1168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Freeze-Dried Poecilobdella manillensis Powder Regulates Cholesterol Homeostasis to Alleviate Hyperlipidemia"],"prefix":"10.3390","volume":"16","author":[{"given":"Dezhi","family":"Yang","sequence":"first","affiliation":[{"name":"Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture and Life Sciences, Kunming University, Kunming 650214, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingmei","family":"Hu","sequence":"additional","affiliation":[{"name":"Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture and Life Sciences, Kunming University, Kunming 650214, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Shi","sequence":"additional","affiliation":[{"name":"Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture and Life Sciences, Kunming University, Kunming 650214, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiquan","family":"Lin","sequence":"additional","affiliation":[{"name":"Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture and Life Sciences, Kunming University, Kunming 650214, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuihua","family":"Fu","sequence":"additional","affiliation":[{"name":"Qujing Lichi Agricultural Technology Development Co., Ltd., Qujing 655100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Yunnan International Joint Laboratory of Digital Conservation and Germplasm Innovation and Application of China-Laos Tea Resources, Pu\u2019er University, Pu\u2019er 665000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoju","family":"Zou","sequence":"additional","affiliation":[{"name":"College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxu","family":"Bi","sequence":"additional","affiliation":[{"name":"Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture and Life Sciences, Kunming University, Kunming 650214, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7509-6209","authenticated-orcid":false,"given":"Zichao","family":"Liu","sequence":"additional","affiliation":[{"name":"Engineering Research Center for Exploitation and Utilization of Leech Resources in Universities of Yunnan Province, School of Agriculture and Life Sciences, Kunming University, Kunming 650214, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s12944-026-02983-6","article-title":"Hypertriglyceridaemia and its multifaceted mechanisms driving atherosclerotic cardiovascular disease","volume":"25","author":"Li","year":"2026","journal-title":"Lipids Health Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Aleksandrowicz, M., Konop, M., Rybka, M., Mazurek, \u0141., Stradczuk-Mazurek, M., Kciuk, M., B\u0105dzy\u0144ska, B., Dobrowolski, L., and Kuczeriszka, M. (2025). Dysfunction of microcirculation in atherosclerosis: Implications of nitric oxide, oxidative stress, and inflammation. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136467"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1007\/s11357-025-01578-w","article-title":"Effects of life-long hyperlipidaemia on age-dependent development of endothelial dysfunction in humanised dyslipidaemic mice","volume":"47","author":"Bar","year":"2025","journal-title":"GeroScience"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s43088-025-00694-y","article-title":"PCSK9 molecular bridge between hyperlipidemia and vascular inflammation: Novel insights into PCSK9-centered pathways in atherosclerosis: A comprehensive review","volume":"14","author":"Desouky","year":"2025","journal-title":"Beni-Suef Univ. J. Basic Appl. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"120604","DOI":"10.1016\/j.jep.2025.120604","article-title":"Typhae pollen attenuates atherosclerosis by enhancing vascular endothelium function and lipid metabolism","volume":"355","author":"Kuang","year":"2026","journal-title":"J. Ethnopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1016\/S0140-6736(17)32252-3","article-title":"Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): A prospective cohort study","volume":"390","author":"Dehghan","year":"2017","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"104773","DOI":"10.1016\/j.fbio.2024.104773","article-title":"7-ketocholesterol promotes cholesterol uptake and inflammation in macrophage: Potential mechanisms of dietary COP in atherosclerosis promotion","volume":"61","author":"Huang","year":"2024","journal-title":"Food Biosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/978-90-481-8622-8_8","article-title":"Lipoprotein modification and macrophage uptake: Role of pathologic cholesterol transport in atherogenesis","volume":"Volume 51","author":"Miller","year":"2010","journal-title":"Cholesterol Binding and Cholesterol Transport Proteins"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41579-020-0433-9","article-title":"Gut microbiota in human metabolic health and disease","volume":"19","author":"Fan","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.2174\/1874467209666160112123746","article-title":"Mevalonate cascade and its regulation in cholesterol metabolism in different tissues in health and disease","volume":"10","author":"Hashemi","year":"2017","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41420-024-02030-2","article-title":"Upregulation of rate-limiting enzymes in cholesterol metabolism by PKC\u03b4 mediates endothelial apoptosis in diabetic wound healing","volume":"10","author":"Qin","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107539","DOI":"10.1016\/j.bioorg.2024.107539","article-title":"Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response","volume":"150","author":"Xiao","year":"2024","journal-title":"Bioorg. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16211","DOI":"10.1039\/D3RA01822A","article-title":"Synthetic ditempolphosphatidylcholine liposome-like nanoparticles for anti-oxidative therapy of atherosclerosis","volume":"13","author":"Wang","year":"2023","journal-title":"RSC Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s11658-024-00673-8","article-title":"Maternal high-fat diet orchestrates offspring hepatic cholesterol metabolism via MEF2A hypermethylation-mediated CYP7A1 suppression","volume":"29","author":"Zhang","year":"2024","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s11033-022-07944-7","article-title":"Cloning and functional identification of pmKPI cDNA in Poecilobdella manillensis","volume":"50","author":"Shao","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_16","first-page":"914","article-title":"Species study on Chinese medicine leech and discussion on its resource sustainable utilization","volume":"38","author":"Zhang","year":"2013","journal-title":"China J. Chin. Mater. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"122822","DOI":"10.1016\/j.jchromb.2021.122822","article-title":"Affinity ultrafiltration and UPLC-HR-orbitrap-MS based screening of thrombin-targeted small molecules with anticoagulation activity from Poecilobdella manillensis","volume":"1178","author":"Huang","year":"2021","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, C., Chen, M., Lu, X., Yang, S., Yang, M., Fang, Y., Lai, R., and Duan, Z. (2023). Isolation and characterization of poeciguamerin, a peptide with dual analgesic and anti-thrombotic activity from the Poecilobdella manillensis leech. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311097"},{"key":"ref_19","first-page":"2310","article-title":"The study on methods for removing the fishy odor of freeze-dried Poecilobdella manillensis powder","volume":"39","author":"Zhang","year":"2016","journal-title":"China J. Chin. Mater. Med."},{"key":"ref_20","first-page":"37","article-title":"Study on anti-thrombin activity of Poecilobdella manillensis freeze-dried powder with dfferent reagents teatment","volume":"38","author":"Wei","year":"2015","journal-title":"J. Chengdu Univ. Tradit. Chin. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e38206","DOI":"10.1016\/j.heliyon.2024.e38206","article-title":"The effect and mechanism of freeze-dried powder of Poecilobdella manillensis on improving inflammatory injury of rat glomerular mesangial cells through TXNIP\/NLRP3 pathway","volume":"10","author":"Sun","year":"2024","journal-title":"Heliyon"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3488","DOI":"10.3748\/wjg.v30.i29.3488","article-title":"Leech Poecilobdella manillensis protein extract ameliorated hyperuricemia by restoring gut microbiota dysregulation and affecting serum metabolites","volume":"30","author":"Liu","year":"2024","journal-title":"World J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102706","DOI":"10.1016\/j.ebiom.2020.102706","article-title":"Macrophage-derived myeloid differentiation protein 2 plays an essential role in ox-LDL-induced inflammation and atherosclerosis","volume":"53","author":"Chen","year":"2020","journal-title":"eBioMedicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5245308","DOI":"10.1155\/2020\/5245308","article-title":"Mechanistic insights into the oxidized low-density lipoprotein-induced atherosclerosis","volume":"2020","author":"Khatana","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s11130-022-00965-4","article-title":"A novel peptide isolated from microalgae isochrysis zhanjiangensis exhibits anti-apoptosis and anti-inflammation in ox-LDL induced HUVEC to improve atherosclerosis","volume":"77","author":"Pei","year":"2022","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wang, Y., Jia, Q., Zhang, Y., Wei, J., and Liu, P. (2020). Taoren honghua drug attenuates atherosclerosis and plays an anti-inflammatory role in ApoE knock-out mice and RAW264.7 cells. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.01070"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1007\/s10735-025-10595-0","article-title":"Marein alleviates atherosclerosis by inhibiting macrophage ferroptosis through activating NRF2 pathway","volume":"56","author":"Zhao","year":"2025","journal-title":"J. Mol. Histol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","article-title":"The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments","volume":"55","author":"Bustin","year":"2009","journal-title":"Clin. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"W201","DOI":"10.1093\/nar\/gkw253","article-title":"MBROLE 2.0-functional enrichment of chemical compounds","volume":"44","author":"Pazos","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.athplu.2025.12.004","article-title":"Poecilobdella manillensis ameliorates atherosclerosis by inhibiting endothelial cell pyroptosis","volume":"63","author":"Guo","year":"2026","journal-title":"Atheroscler. Plus"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.bbrc.2014.10.135","article-title":"An extract from medical leech improve the function of endothelial cells in vitro and attenuates atherosclerosis in ApoE null mice by reducing macrophages in the lesions","volume":"455","author":"Wang","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cao, H., Jia, Q., Yan, L., Chen, C., Xing, S., and Shen, D. (2019). Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20236093"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6939","DOI":"10.12998\/wjcc.v12.i36.6939","article-title":"Potential of traditional chinese medicine lyophilized powder of Poecilobdella manillensis in the treatment of hyperuricemia","volume":"12","author":"Huang","year":"2024","journal-title":"World J. Clin. Cases"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"C7","DOI":"10.1016\/j.jacc.2005.09.068","article-title":"Pathogenesis of atherosclerosis","volume":"47","author":"Falk","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"115985","DOI":"10.1016\/j.bcp.2023.115985","article-title":"Pharmacological modulation of cholesterol 7\u03b1-hydroxylase (CYP7A1) as a therapeutic strategy for hypercholesterolemia","volume":"220","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zi\u00f3\u0142kiewicz, A., Kasprzak-Drozd, K., Rusinek, R., Markut-Miot\u0142a, E., and Oniszczuk, A. (2023). The influence of polyphenols on atherosclerosis development. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087146"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"The Lancet Diabetes & Endocrinology (2025). World heart day: Diabetes and cardiovascular risk. Lancet Diabetes Endocrinol., 13, 897.","DOI":"10.1016\/S2213-8587(25)00296-7"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25080","DOI":"10.1021\/acsami.2c02354","article-title":"A ROS-responsive simvastatin nano-prodrug and its fibronectin-targeted co-delivery system for atherosclerosis treatment","volume":"14","author":"Zhao","year":"2022","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"BSR20204216","DOI":"10.1042\/BSR20204216","article-title":"Gualou xiebai banxia decoction ameliorates poloxamer 407-induced hyperlipidemia","volume":"41","author":"Luo","year":"2021","journal-title":"Biosci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3892\/ijmm.2021.5020","article-title":"Oxymatrine attenuates oxidized low-density lipoprotein-induced HUVEC injury by inhibiting NLRP3 inflammasome-mediated pyroptosis via the activation of the SIRT1\/Nrf2 signaling pathway","volume":"48","author":"Jin","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e70549","DOI":"10.1002\/fsn3.70549","article-title":"Lycopene alleviates lipid dysregulation, oxidative stress, and hypercholesterolemia in obese rats subjected to a high-fat diet","volume":"13","author":"Noreen","year":"2025","journal-title":"Food Sci. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.20463\/jenb.2016.03.20.1.5","article-title":"Impact of eight weeks endurance training on biochemical parameters and obesity-induced oxidative stress in high fat diet-fed rats","volume":"20","author":"Emami","year":"2016","journal-title":"J. Exerc. Nutr. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"109285","DOI":"10.1016\/j.fbio.2026.109285","article-title":"\u03b1-lactalbumin peptide GINY ameliorates lipid metabolism disorders and gut microbiota dysbiosis in high-fat diet-fed mice","volume":"82","author":"Yang","year":"2026","journal-title":"Food Biosci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kattan, S.W., Almars, A.I., Tounsi, W.A., Turkistani, A.A., Mohamed, A.M., Elghareeb, M.M., Elmorsy, E.M., and Ali, S.H.E. (2026). Silymarin-loaded phytosomal nanoparticles mitigate dyslipidemia, oxidative damage, and hepatic injury in high-fat diet-induced metabolic dysfunction-associated steatotic liver disease in rats. BMC Gastroenterol.","DOI":"10.1186\/s12876-026-05004-z"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1093\/eurheartj\/ehx144","article-title":"Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the european atherosclerosis society consensus panel","volume":"38","author":"Ference","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.cell.2011.04.005","article-title":"Macrophages in the pathogenesis of atherosclerosis","volume":"145","author":"Moore","year":"2011","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/343425a0","article-title":"Regulation of the mevalonate pathway","volume":"343","author":"Goldstein","year":"1990","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1059344","article-title":"Structural mechanism for statin inhibition of HMG-CoA reductase","volume":"292","author":"Istvan","year":"2001","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"18707","DOI":"10.1074\/jbc.R113.479808","article-title":"Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)","volume":"288","author":"Sharpe","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41392-022-00955-7","article-title":"Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention","volume":"7","author":"Kong","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"127109","DOI":"10.1016\/j.talanta.2024.127109","article-title":"Simultaneous metabolomics and lipidomics analysis based on 4in1 online analysis system reveal metabolic signatures in atherosclerotic mice","volume":"283","author":"Ding","year":"2025","journal-title":"Talanta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s42255-024-01203-8","article-title":"Cellular and organismal function of choline metabolism","volume":"7","author":"Kenny","year":"2025","journal-title":"Nat. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"s27","DOI":"10.5604\/01.3001.0010.5495","article-title":"Cholesterol and lipoprotein metabolism and atherosclerosis: Recent advances In reverse cholesterol transport","volume":"16","author":"Wang","year":"2017","journal-title":"Ann. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"100504","DOI":"10.1016\/j.jlr.2024.100504","article-title":"Spatial lipidomics of coronary atherosclerotic plaque development in a familial hypercholesterolemia swine model","volume":"65","author":"Slijkhuis","year":"2024","journal-title":"J. Lipid Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Zhang, C., Wu, X., Shi, P., Ma, H., Fang, F., Feng, Q., Zhao, S., Zhang, R., Huang, J., and Xu, X. (2023). Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1066758"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1016\/j.sjbs.2020.06.010","article-title":"Inhibitory effects of tangeretin and trans-ethyl caffeate on the HMG-CoA reductase activity: Potential agents for reducing cholesterol levels","volume":"27","author":"Pangestika","year":"2020","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5226","DOI":"10.1021\/acs.jafc.1c01463","article-title":"Four citrus flavanones exert atherosclerosis alleviation effects in ApoE\u2212\/\u2212 mice via different metabolic and signaling pathways","volume":"69","author":"Wang","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"118209","DOI":"10.1016\/j.jep.2024.118209","article-title":"Dan-shen yin promotes bile acid metabolism and excretion to prevent atherosclerosis via activating FXR\/BSEP signaling pathway","volume":"330","author":"Sheng","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"154220","DOI":"10.1016\/j.phymed.2022.154220","article-title":"Qing-xin-jie-yu granule alleviates atherosclerosis by reshaping gut microbiota and metabolic homeostasis of ApoE\u2212\/\u2212 mice","volume":"103","author":"Wang","year":"2022","journal-title":"Phytomedicine"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:41:08Z","timestamp":1787564468000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":61,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["biom16081168"],"URL":"https:\/\/doi.org\/10.3390\/biom16081168","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]}}}