Ginseng, a traditional herb with a history spanning thousands of years in Asian culture, has gained widespread recognition for its valuable pharmacological properties. The primary active constituents of ginseng, ginsenosides, are renowned for their diverse biological activities, including cardioprotective, anti-tumor, anti-inflammatory, and neuroprotective effects. However, the therapeutic potential of ginsenosides is often constrained by their low bioavailability in their native forms. During metabolism, ginsenosides undergo biotransformation by intestinal microbiota and enzymes, yielding metabolites with significantly enhanced bioavailability. Thus, to enhance the utility of ginsenosides as pharmaceutical agents and health products, it is essential to deepen our understanding of their metabolic processes and bioavailability in vivo. This review provides a comprehensive analysis of the ginsenoside content in ginseng and the modifications that occur during in vivo metabolism. Particular emphasis is placed on the plasma concentrations of ginsenoside metabolites, as well as the pivotal roles of specific microorganisms and enzymes in the metabolic process. Additionally, the pharmacokinetics of ginsenosides in the bloodstream following metabolism and their associated pharmacological activities are thoroughly examined. By offering a detailed exploration of ginsenosides' metabolism and pharmacodynamics, this review aims to advance our understanding of their therapeutic potential and support future research and drug development initiatives.

Colorectal cancer is the third most common cancer worldwide and the fourth leading cause of cancer death. Protopanaxatriol (PPT), one of the main active metabolic ginsenosides of ginseng, has been found to have neuroprotective and anti-inflammatory effects, but its role in regulating colon cancer development remained unclear. We sought to confirm the inhibitory effect of PPT on colon cancer cells and elucidate its target and mechanism. MTT assay, colony formation, invasion, migration assays, cell apoptosis, and cell-cycle analysis were performed. Quantitative real-time PCR, Western blotting, bioinformatic analysis using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology, and cellular thermal shift assay experiments were also employed. PPT can inhibit the cloning, migration, invasion, and proliferation of colon cancer cells. PPT can increase the number of apoptotic bodies, promote the expression of the apoptotic proteins caspase-9 and caspase-3, induce apoptosis, and inhibit cell proliferation. In addition, by regulating cyclin, PPT can increase the expression of p21 and p27 proteins and inhibit the expression of the cyclin D1 protein, thereby inhibiting the G1/S transformation in the cell cycle. We further demonstrated that PPT can target AKT, reduce its protein expression, and reduce tumor progression and the expression of inflammatory factors caused by AKT high expression (TNF-α, IL-1β, and IL-6), thereby playing a role in inhibiting colon cancer progression. We are the first to demonstrate that the ginsenoside PPT can inhibit the activity of colon cancer cells by directly binding AKT.

Ginsenosides from Panax ginseng Meyer and their microbiota-derived metabolites have been explored as adjuncts in oncology, with pleiotropic activities across tumor-intrinsic and microenvironmental pathways. This review focuses on representative metabolites (Rg3, Rh2 and compound K) and summarizes mechanistic evidence for apoptosis and cell-cycle control, metabolic reprogramming (Warburg-type glycolysis), and epigenetic regulation (miRNA/lncRNA-linked programs), together with immunomodulatory effects in the tumor microenvironment. A central translational constraint is pharmacokinetics and the “microbiota gatekeeping” effect: many parent ginsenosides show limited oral absorption and require microbiota-mediated deglycosylation, resulting in delayed and variable systemic exposure across individuals. To address this bottleneck, we discuss pragmatic translational directions including bioconversion/pre-transformation to enrich active metabolites, biomimetic delivery platforms such as ginseng-derived exosome-like nanoparticles to improve exposure and tissue uptake, and mechanism-guided combinations (e.g., with immune checkpoint blockade). Finally, we outline how biomarker-informed stratification and AI/ML-enabled, hypothesis-generating optimization of delivery/formulation may support more predictable clinical development.