20(S)-Protopanaxatriol Alleviates Gastritis by Attenuating Oxidative Stress and Inflammatory Responses via Inhibition of PI3K/AKT and JAK/STAT3 Pathways

Inflammation is a fundamental protective response of the body; however, chronic or excessive inflammation can perturb immune homeostasis and elevate the risk of cardiovascular, metabolic, and oncological diseases. Protopanaxatriol (PPT), a principal bioactive metabolite of Panax ginseng ginsenosides, has demonstrated diverse pharmacological activities, including protective effects in colon cancer, dermatological disorders, and hepatic injury. Despite these observations, the molecular mechanisms underlying PPT’s modulation of inflammatory processes remain insufficiently characterized. This study aims to evaluate the anti-inflammatory potential of PPT and elucidate mechanistic pathways. Potential targets and signaling pathways were predicted using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The anti-inflammatory activity of PPT was assessed in vitro through nitric oxide (NO) assays, MTT assay, Neutral Red staining, luciferase reporter assays, ROS quantification, RT-PCR, Real-time PCR and Western blotting. In vivo efficacy was examined in an HCl/EtOH-induced gastritis model, with histopathological changes analyzed via hematoxylin and eosin (H&E) staining. PPT markedly attenuated LPS-induced inflammatory responses at non-cytotoxic concentrations, suppressing NO production and reducing expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). In vivo , PPT mitigated gastric mucosal injury in the HCl/EtOH model. Mechanistic investigations revealed that PPT selectively inhibited NF-κB (p65/p50) and AP-1 (c-Jun/c-Fos) activation, downregulation of the JAK-STAT3 pathway, and reduction of ROS accumulation and oxidative stress, collectively mediating its anti-inflammatory effects. PPT exerts potent anti-inflammatory effects by inhibiting PI3K/AKT and JAK-STAT3 signaling and alleviating oxidative stress. These findings support PPT as a promising candidate for the development of novel anti-inflammatory therapeutics.