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Pyruvate carboxylase promotes glycolysis and progression of endometriosis by activating the AKT pathway

ABSTRACT: Pyruvate carboxylase (PC) is a key metabolic enzyme, and its role in endometriosis progression remains unclear. This study aimed to investigate whether PC promotes endometriosis progression and explore its underlying mechanisms. Immunohistochemical analysis was used to detect PC expression in patient tissues; PC was knocked down or overexpressed in immortalized human endometriotic stromal cells (ihESCs) to assess proliferation (colony formation, EdU assay) and migration (Transwell assay) changes. Quasi-targeted metabolomics and RNA sequencing were applied to explore the effects of PC knockdown on downstream metabolism and pathways, and Western blotting was used to detect related protein changes. Additionally, an allogeneic endometriosis model in C57BL/6J female mice with AAV9-mediated PC overexpression was established to verify PC's in vivo effect. Results showed that PC expression was significantly upregulated in endometriosis patients; in vitro and in vivo experiments confirmed PC promotes endometriosis progression. Quasi-targeted metabolomics revealed PC enhances ihESCs glycolysis, while RNA sequencing and western blotting identified PC activates the PI3K-AKT pathway. Further studies with AKT agonist (SC79) and inhibitor (AZD5363) demonstrated PC promotes endometriosis glycolysis and progression via the AKT pathway. Moreover, PC inhibitors ZY-444 and octyl gallate inhibited ihESCs proliferation and migration, and ZY-444 suppressed endometriotic lesion growth in mice.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316028 | GEO | 2026/01/11

REPOSITORIES: GEO

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Project description:Background Reduced endometrial receptivity is a major factor for impaired fertility in endometriosis (EMS). Endometrial deposition of collagen I proteins may account for poor endometrial receptivity in endometriosis. Methods We investigated the expression of collagen I expression in endometrium of endometriosis patients and in constructed EMS mice model. Effect of collagen I on ESCs was evaluated. Co-culture of exosomes with ESCs was conducted to evaluate the uptake of exosomes by different endometrial cell lines and the effect on decidualization of eutopic ESCs and embryo implantation. MiRNA expression profiles were compared between ectopic ESC derived exosomes and eutopic ESC derived exosomes. Luciferase reporter and its mutant plasmids were applied to confirm the direct target of miR-25-3p. Findings Here we found endometrial collagen I deposition with impaired decidualization in endometriosis patients and EMS mice model. Treatment of collagen I with ESCs contributed to impaired decidualization and inhibited BLS expansion in vitro. Endometriotic stromal cell-derived exosomes were detected in eutopic endometrium and the ectopic endometrial stromal cell derived exosomes were more taken-up by the same cell line in eutopic endometrium. Treatment of endometriotic stromal cell-derived exosomes increased the expression of endometrial collagen I in vitro and in vivo, while inhibited BLS expansion. Exosomal miR-25-3p was significantly increased in endometriotic stromal cell-derived exosomes compared with control group, and PTEN is a certain target of miR-25-3p. The promotion of endometrial miR-25-3p significantly increased collagen I expression in vitro through the PTEN/Akt pathway. Interpretation These results suggested that endometriotic stromal cell-derived exosomal miR-25-3p played key role in inducing endometrial collagen I deposition to impair embryo expansion in endometriosis via PTEN/Akt pathway. Funding National Nature Science Foundation of China (82271702), National Natural Science Foundation of China (81771537). Keywords: endometriosis; exosome; collagen I; miRNA; collagen deposition

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Pyruvate carboxylase promotes glycolysis and progression of endometriosis by activating the AKT pathway

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