Weiyan Tongluo Granules attenuate gastric intestinal metaplasia through PPARγ/NF-κB/CDX2 signaling pathway.

[BACKGROUND] Gastric intestinal metaplasia (GIM) is a precancerous condition characterized by the replacement of gastric mucosa with intestinal-like epithelium, posing a considerable risk for gastric cancer with no effective cure available. Weiyan Tongluo Granules (WYTLG), a traditional Chinese medicine (TCM) formulation, has demonstrated clinical potential in managing GIM, though its mechanisms remain elusive. This study sought to systematically investigate the therapeutic effects of WYTLG on GIM and its molecular mechanism.

[METHODS] An integrative strategy combining in vivo, in vitro, and in silico methodologies was conducted. We identified the main compounds of WYTLG and then established GIM models in rats and cells through induction using N-methyl-N'-nitro-N-nitrosoguanidine and deoxycholic acid to evaluate its pharmacological effects. Transcriptomic analysis was performed on gastric tissues to fully elucidate the underlying mechanisms. In addition, molecular docking analysis was employed to predict the interactions between key compounds of WYTLG and potential targets. The mechanistic findings were further investigated and validated through cellular-level experiments.

[RESULTS] A total of 29 components were identified in WYTLG. Treatment with WYTLG dose-dependently improved gastric injury and GIM in rat models, accompanied by restoration of gastric function, attenuation of pathological alterations, and regulation of GIM-related biomarkers. WYTLG treatment significantly alleviated inflammatory responses and enhanced resistance to apoptosis in gastric glands. Consistent with the in vivo findings, WYTLG-containing serum exerted comparable anti-GIM effects in vitro. Transcriptomic analysis highlighted the PPARγ/NF-κB signaling pathway as a key mechanism underlying the effects of WYTLG. These finding was further corroborated by intervention studies using GW9662, a PPARγ antagonist, TNF-α, an NF-κB activator, and si-PPARγ, all of which largely attenuated the therapeutic effects. Furthermore, molecular docking analysis demonstrated favorable binding affinities between active WYTLG components and key targets within this pathway.

[CONCLUSION] WYTLG attenuates the progression of GIM through modulation​ of the PPARγ/NF-κB/CDX2 axis, providing a prospective strategy for preventing gastric malignant transformation.