蒲公英甾醇通过靶向PTP1B/PKM2/NF-κB信号通路抑制H. pylori诱导的胃炎和胃癌

Chronic Helicobacter pylori infection is a primary cause of gastritis, peptic ulcers, and gastric cancer (GC), creating a demand for novel therapeutic agents that address both inflammation and tumor progression. Taraxasterol (TAX) has demonstrated significant therapeutic potential against both gastritis and gastric cancer (GC). In vitro , TAX effectively alleviated H. pylori-induced gastritis by reducing intracellular bacterial load and attenuating the inflammatory response, specifically by decreasing TNF-alpha levels and reactive oxygen species, and inhibiting the NF-κB signaling pathway (IKKalpha and P65 phosphorylation). TAX did not directly inhibit H. pylori growth, suggesting its mechanism is primarily anti-inflammatory. Beyond gastritis, TAX exhibited potent anti-cancer effects on GC cell lines (AGS and MGC803), dose-dependently inhibiting their proliferation and colony formation. Mechanistically, computational and experimental analyses (SPR, DARTS, CETSA) identified Protein Tyrosine Phosphatase 1B (PTP1B) as a direct target of TAX. PTP1B, found to be highly expressed in gastritis and GC tissues and associated with poor prognosis, had its phosphatase activity inhibited by TAX. Further studies showed that PTP1B knockdown inhibited GC cell proliferation and that TAX's anti-proliferative effects were partially mediated through PTP1B, modulating the PTP1B/PKM2/NF-κB signaling pathway. In vivo , TAX successfully inhibited H. pylori and/or alcohol-induced gastritis in mice, reducing inflammation, lymphocyte infiltration, and cytokine levels. Crucially, TAX also suppressed tumor growth in gastric cancer patient-derived xenograft (PDX) models. These findings collectively highlight TAX as a promising therapeutic agent for both gastritis and gastric cancer, primarily through its anti-inflammatory properties and its targeted inhibition of PTP1B.