Ginsenoside-empowered anti-inflammation: Multi-pathway regulation, structure-activity relationships, and potentiation strategies

As the major active constituents of Panax species, ginsenosides exert multi-target synergistic anti-inflammatory effects by modulating multiple inflammatory signaling pathways, including NF-κB, MAPK, PI3K/Akt, JAK/STAT3, TLR4/MyD88, and Keap1-Nrf2. Structure-activity relationship studies have revealed clear trends: protopanaxadiol-type ginsenosides outperform protopanaxatriol-type, the S configuration at C-20 is more potent than the R configuration, and a reduction in the number of sugar moieties markedly enhances activity. Rare ginsenosides, characterized by simplified structures, consequently exhibit superior bioavailability. To address the inherently low natural abundance and poor solubility of rare ginsenosides, physical, biological, and chemical conversion technologies can achieve efficient and targeted transformation of prototype ginsenosides into rare ginsenosides. Moreover, the application of delivery systems such as nanocarriers and liposomes can further improve their solubility, targeting, and ultimately their anti-inflammatory efficacy. This review systematically summarizes the molecular mechanisms by which ginsenosides regulate inflammatory signaling pathways, their structure-activity relationships, and strategies for activity enhancement, aiming to provide a reference for promoting the clinical translation and application of ginsenosides in inflammation-related diseases.