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

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.