Pyruvate carboxylase promotes progression of endometriosis by activating the AKT pathway

Wu Y, Yongfeng Wu, Ye X, Xiaoye Ye, Ou Jin, Jin O, Liu B, Beibei Liu, Shuchen Yu, Yu S, Aolin Zheng, Zheng A, Lv F, Fei Lv, Yingling Zheng, Zheng Y, Fengjuan Liu, Liu F, Xu S, Song Xu, Ke Zhang, Zhang K, Jin C, Chunyu Jin, Tong J, Jinyi Tong
Reproductive BioMedicine Online · 2026 · vol. 53(5) , pp. 105889 · doi:10.1016/j.rbmo.2026.105889 · PMID:42641507 · W7171737896
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Pyruvate carboxylase promotes the progression of endometriosis by activating the AKT signaling pathway.

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Abstract

RESEARCH QUESTION: Does pyruvate carboxylase drive the progression of endometriosis, and, if so, what is the underlying mechanism? DESIGN: The expression of pyruvate carboxylase in clinical endometrial specimens was examined via immunohistochemistry. After knockdown or overexpression of pyruvate carboxylase in immortalized human endometriotic stromal cells (ihESC), cell proliferation and migration were assessed using 5-ethynyl-2'-deoxyuridine (EdU), colony formation and Transwell assays. Quasi-targeted metabolomics, RNA sequencing and western blotting were adopted to explore downstream molecular changes, and an allogeneic mouse endometriotic model was applied for in-vivo functional verification. RESULTS: Expression of pyruvate carboxylase was up-regulated significantly in eutopic and ectopic endometrial tissues of patients with endometriosis compared with controls (P = 0.022 and P < 0.001, respectively). In-vitro and in-vivo experiments showed that pyruvate carboxylase promoted the progression of endometriosis. In addition, quasi-targeted metabolomics showed that knockdown of pyruvate carboxylase decreased the abundance of glycolytic metabolites in ihESC. Furthermore, RNA sequencing and western blotting identified that pyruvate carboxylase enhanced activity of the phosphoinositide-3-kinase-AKT pathway. Using AKT agonist (SC79) and inhibitor (AZD5363), pyruvate carboxylase was shown to modulate the expression of glycolytic enzymes and the progression of endometriosis through the AKT pathway. Finally, pyruvate carboxylase inhibitors ZY-444 and octyl gallate attenuated the progression of endometriosis. CONCLUSIONS: Pyruvate carboxylase is up-regulated significantly in eutopic and ectopic endometrial tissues from patients with endometriosis, and modulates the expression of glycolytic enzymes as well as the progression of endometriosis via activation of the AKT pathway. These findings provide mechanistic insight into the metabolic reprogramming underlying the pathogenesis of endometriosis.

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organisms 2
human transgenic mice
chemicals 2
2'-deoxyuridine octyl gallate

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