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(2) Methods: We established a high-fat diet (HFD)-induced hypercholesterolemia (HC) mouse model and performed GP intervention. An integrated multi-omics approach, combining transcriptomics and proteomics, was utilized to comprehensively analyze GP\u2019s effects on the expression of genes and proteins associated with hepatic cholesterol synthesis, transport, and steroid hormone metabolism. (3) Results: HFD induced significant dysregulation, with 48 steroidogenesis pathway-related genes and 35 corresponding proteins exhibiting altered expression in HC mouse livers. GP treatment remarkably reversed these HFD-induced abnormalities, significantly restoring the expression levels of 42 genes and 14 proteins. Multi-omics integration identified seven critical genes\/proteins\u2014Cyp3a25, Fdft1, Tm7sf2, Hmgcs1, Fdps, Mvd, and Pmvk\u2014that were consistently and significantly regulated by GP at both transcriptional and translational levels. Furthermore, correlation analyses demonstrated that Cyp3a25 was significantly negatively correlated with serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), whereas Fdft1, Tm7sf2, Hmgcs1, Fdps, Mvd, and Pmvk showed significant positive correlations. (4) Conclusions: GP effectively ameliorates cholesterol dyshomeostasis through a multi-targeted mechanism in the liver. It inhibits endogenous cholesterol synthesis by downregulating key enzymes (Hmgcs1, Fdft1, Pmvk, Mvd, Fdps, Tm7sf2), promotes cholesterol efflux and transport (upregulating Abca1, ApoB), and accelerates steroid hormone metabolism (upregulating Cyp3a11, Cyp3a25). These findings provide robust scientific evidence for the development of GP as a safe and effective novel therapeutic agent for hypercholesterolemia.<\/jats:p>","DOI":"10.3390\/biom15081205","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T14:46:04Z","timestamp":1755787564000},"page":"1205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrated Multi-Omics Investigation of Gypenosides\u2019 Mechanisms in Lowering Hepatic Cholesterol"],"prefix":"10.3390","volume":"15","author":[{"given":"Qin","family":"Jiang","sequence":"first","affiliation":[{"name":"Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Guizhou Engineering Research Center for Orchid Medicinal Plant Breeding and Efficient Application, Zunyi Medical University, Zunyi 563000, 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