Wenshen Xiaozheng Tang ameliorates endometriosis by interrupting the lactate/H3K9la-mediated crosstalk between ectopic endometrial stromal cells and macrophages

WXT significantly reduced ectopic lesion volume, alleviated peritoneal adhesions, and decreased the proportion of M2 macrophages in both lesion tissues and peritoneal fluid, along with reduced lactate accumulation and suppressed M2-associated cytokine secretion. Single-cell transcriptomic analysis revealed enhanced glycolytic activity in eESCs and a positive correlation between M2 macrophage polarization and lactate-sensing gene signatures. WXT-containing serum inhibited eESC-derived lactate production, reduced H3K9la levels in macrophages, and blocked lactate-induced M2 polarization. Through UPLC-Q-TOF-MS/MS and molecular docking screening, we identified tormentic acid as a key absorbed component with strong predicted binding to both GLUT1 (a key glycolytic transporter) and p300 (a key regulator of histone lactylation). Tormentic acid reproduced the effects of WXT-containing serum, suppressing lactate production, reducing H3K9la levels, and attenuating M2 polarization. CUT&Tag and ChIP-qPCR further revealed that tormentic acid reduced H3K9la enrichment at the WNT2B promoter and suppressed its expression, defining a lactate-H3K9la-WNT2B axis through which tormentic acid ameliorates endometriosis.