{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T12:30:55Z","timestamp":1787574655815,"version":"build-2736575974"},"reference-count":25,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a progressive condition predisposing to cirrhosis and hepatocellular carcinoma, with prevalence rising globally. Yet effective therapies remain limited. Wuzhi Dripping Pills (WZDP), derived from Schisandra sphenanthera, possess hepatoprotective and anti-inflammatory properties, though their efficacy against MASLD remains unexplored. Methods: Network pharmacology predicted active ingredients and targets, followed by KEGG enrichment analysis. A high-fat diet MASLD rat model was established to evaluate WZDP effects on weight, liver index, and serum markers. Serum metabolomic profiling via UPLC-MS\/MS, combined with multivariate statistics and KEGG annotation, identified perturbed pathways. Results: Twelve bioactive compounds and 434 WZDP targets were retrieved, of which 74 intersected with 838 MASLD-associated genes. Enrichment implicated AGE-RAGE, insulin resistance, and HIF-1 signaling. In vivo, WZDP significantly improved anthropometric and biochemical parameters. Metabolomic analysis distinctly separated WZDP-treated from model groups, highlighting phospholipase D signaling as a key differential pathway. Conclusions: This integrative approach confirms that WZDP confers therapeutic benefits in MASLD through coordinated regulation of neuroactive ligand\u2013receptor interaction, bile acid biosynthesis, phospholipase D signaling, and arginine\u2013proline metabolism. Our findings furnish a molecular and metabolic rationale for further mechanistic studies and drug discovery efforts.<\/jats:p>","DOI":"10.3390\/metabo16090601","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T11:47:19Z","timestamp":1787572039000},"page":"601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating Network Pharmacology and Metabolomics to Decipher the Mechanisms Underlying the Therapeutic Effects of Wuzhi Dripping Pills Against MASLD"],"prefix":"10.3390","volume":"16","author":[{"given":"Huijun","family":"Wang","sequence":"first","affiliation":[{"name":"School of Medicine, Pingdingshan University, Pingdingshan 467000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Medicine, Pingdingshan University, Pingdingshan 467000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangkang","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Medicine, Pingdingshan University, Pingdingshan 467000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoxing","family":"Xiao","sequence":"additional","affiliation":[{"name":"College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyi","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7644-9598","authenticated-orcid":false,"given":"Xiangjun","family":"Qiu","sequence":"additional","affiliation":[{"name":"College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang 471023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yang, M., Xiao, X., Mei, J., Pubu, C., and Gong, Q. (2025). MASLD: Insights on the role of folate in hepatic lipid metabolism. Front. Nutr., 12.","DOI":"10.3389\/fnut.2025.1583674"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1007\/s00204-025-04052-w","article-title":"Lipogenesis and MASLD: Re-thinking the role of SREBPs","volume":"99","author":"Nakagawa","year":"2025","journal-title":"Arch. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S2213-8587(24)00318-8","article-title":"Metabolic dysfunction-associated steatotic liver disease: Heterogeneous pathomechanisms and effectiveness of metabolism-based treatment","volume":"13","author":"Stefan","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12944-024-02108-x","article-title":"Updated mechanisms of MASLD pathogenesis","volume":"23","author":"Li","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1097\/CM9.0000000000003629","article-title":"MASLD development: From molecular pathogenesis toward therapeutic strategies","volume":"138","author":"Yang","year":"2025","journal-title":"Chin. Med. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/ueg2.12525","article-title":"Therapeutic management of metabolic dysfunction associated steatotic liver disease","volume":"12","author":"Zeng","year":"2024","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/dom.16496","article-title":"Management of metabolic dysfunction-associated steatotic liver disease (MASLD)-An expert consensus statement from Indian diabetologists\u2019 perspective","volume":"27","author":"Zargar","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Tao, S., Lei, Y.Q., Tan, Y.M., Yang, Y.B., and Xie, W.N. (2024). Chinese herbal formula in the treatment of metabolic dysfunction-associated steatotic liver disease: Current evidence and practice. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1476419"},{"key":"ref_9","first-page":"e18715303361217","article-title":"Review of Traditional Chinese Medicine in the Treatment of Non-Alcoholic Fatty Liver Disease","volume":"26","author":"Lu","year":"2025","journal-title":"Endocr. Metab. Immune Disord.-Drug Targets"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"156348","DOI":"10.1016\/j.phymed.2024.156348","article-title":"Schisandra sphenanthera extract modulates sweet taste receptor pathway, IRS\/PI3K, AMPK\/mTOR pathway and endogenous metabolites against T2DM","volume":"136","author":"Feng","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"118300","DOI":"10.1016\/j.jep.2024.118300","article-title":"Petroleum ether extract of Schisandra sphenanthera prevents hyperglycemia and insulin resistance in association with modulation of sweet taste receptors and gut microbiota in T2DM rats","volume":"331","author":"Jiang","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"119801","DOI":"10.1016\/j.jep.2025.119801","article-title":"Schisandra chinensis lignans ameliorate hepatic inflammation and steatosis in methionine choline-deficient diet-fed mice by modulating the gut-liver axis","volume":"348","author":"Yan","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.foodchem.2011.03.030","article-title":"New and bioactive lignans from the fruits of Schisandra sphenanthera","volume":"128","author":"Huang","year":"2011","journal-title":"Food Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1124\/dmd.115.066969","article-title":"Hepatoprotective effects of Schisandra sphenanthera extract against lithocholic acid-induced cholestasis in male mice are associated with activation of the pregnane X receptor pathway and promotion of liver regeneration","volume":"44","author":"Zeng","year":"2016","journal-title":"Drug Metab. Dispos."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, S., Su, Y., Han, A., Qi, H., Zhao, J., and Qiu, X. (2025). UPLC-MS\/MS Metabolomics Reveals Babao Dan\u2019s Mechanisms in MASH Treatment with Integrating Network Pharmacology and Molecular Docking. Pharmaceuticals, 18.","DOI":"10.3390\/ph18081111"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5761","DOI":"10.2147\/DDDT.S533394","article-title":"Mechanism of SiMiaoWan in the Treatment of Hyperuricemia Based on Serum Metabolomics","volume":"19","author":"Guo","year":"2025","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liu, S., Zhu, Y., Wang, W., Zhang, X., Gao, L., and Qiu, X. (2025). Mechanism Study on the Preventive Effect of ELITEA Compound Tea on Hyperuricemia in Rats Based on Serum Untargeted Metabolomics. Metabolites, 15.","DOI":"10.3390\/metabo15050336"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"342103","DOI":"10.1016\/j.aca.2023.342103","article-title":"Comparing univariate filtration preceding and succeeding PLS-DA analysis on the differential variables\/metabolites identified from untargeted LC-MS metabolomics data","volume":"1287","author":"Xu","year":"2024","journal-title":"Anal. Chim. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1124\/pr.114.009217","article-title":"Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer","volume":"66","author":"Bruntz","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"123166","DOI":"10.1016\/j.lfs.2024.123166","article-title":"Phospholipase D2 drives cellular lipotoxicity and tissue inflammation in alcohol-associated liver disease","volume":"358","author":"Guo","year":"2024","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100726","DOI":"10.1016\/j.jhepr.2023.100726","article-title":"Inhibition of phospholipase D1 ameliorates hepatocyte steatosis and non-alcoholic fatty liver disease","volume":"5","author":"Wang","year":"2023","journal-title":"JHEP Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/s41586-021-03832-5","article-title":"Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians","volume":"599","author":"Sato","year":"2021","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/S2468-1253(21)00020-0","article-title":"Non-alcoholic fatty liver disease: A multisystem disease requiring a multidisciplinary and holistic approach","volume":"6","author":"Targher","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"109581","DOI":"10.1016\/j.jnutbio.2024.109581","article-title":"Molecular mechanism and therapeutic significance of essential amino acids in metabolically associated fatty liver disease","volume":"126","author":"Deng","year":"2024","journal-title":"J. Nutr. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1093\/bbb\/zbac197","article-title":"Protamine derived peptide RPR (Arg Pro Arg) ameliorates oleic acid induced lipogenesis via the PepT1 pathway in HepG2 cells","volume":"87","author":"Mijiti","year":"2023","journal-title":"Biosci. Biotechnol. Biochem."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/9\/601\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T12:11:20Z","timestamp":1787573480000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/9\/601"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,22]]},"references-count":25,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["metabo16090601"],"URL":"https:\/\/doi.org\/10.3390\/metabo16090601","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,22]]}}}