Pristimerin ameliorates spasmolytic polypeptide-expressing metaplasia by modulating (p57)-mediated glycolytic reprogramming.

[BACKGROUND] Spasmolytic polypeptide-expressing metaplasia (SPEM) is a gastric precancerous lesion (GPL) with high malignant potential. The ethyl acetate extract of Thunb. effectively ameliorates GPL and gastric cancer progression. Meanwhile, the primary active constituent of this plant, pristimerin, also demonstrates notable antitumor activity.

[AIM] To investigate the therapeutic effects of pristimerin on SPEM and its underlying mechanisms.

[METHODS] Pristimerin was administered to high-dose tamoxifen-induced SPEM mice to assess its effects on pathological progression, glycolytic reprogramming, and (p57) expression. Human gastric epithelial (GES-1) cells were treated with tamoxifen and then with pristimerin or 2-deoxy-D-glucose to demonstrate that pristimerin ameliorates SPEM by regulating glycolytic reprogramming. Furthermore, gastric organoids were treated with N-methyl-N'-nitro-N-nitrosoguanidine/, followed by overexpression or knockdown and then pristimerin, to confirm p57 as the key target through which pristimerin regulates glycolytic reprogramming and reverses SPEM.

[RESULTS] Pristimerin effectively ameliorated gastric mucosal damage and oxyntic atrophy induced by high-dose tamoxifen, suppressed the aberrant upregulation of key glycolytic regulators, SPEM-specific markers, and stem cell markers, and upregulated p57 expression. In tamoxifen-induced GES-1 cells, pristimerin exhibited comparable therapeutic effects. Crucially, glycolysis inhibition in GES-1 cells effectively ameliorated tamoxifen-induced SPEM-associated phenotypes. In gastric organoids, overexpression suppressed glycolytic reprogramming and SPEM phenotype activation, whereas knockdown attenuated pristimerin-mediated inhibition of glycolysis and amelioration of SPEM.

[CONCLUSION] Pristimerin effectively ameliorates gastric mucosal pathological damage and oxyntic atrophy in high-dose tamoxifen-induced SPEM mice, and improves SPEM progression by modulating (p57)-mediated glycolytic reprogramming.