Pyruvate carboxylase promotes SREBP1a-mediated lipid synthesis in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is characterized by late diagnosis and high recurrence, with dysregulated lipid metabolism emerging as a hallmark of progression. Here, we identify pyruvate carboxylase (PC) as a key metabolic driver that promotes lipid synthesis in EOC. PC is upregulated in EOC tissues and correlates with poor prognosis and triglyceride accumulation. Mechanistically, PC enhances acetyl-CoA production, promoting sterol regulatory element-binding protein 1a (SREBP1a) acetylation and stability, and increases α-ketoglutarate levels to facilitate ten-eleven translocation 1 (TET1)-mediated DNA hydroxymethylation at lipid synthetase gene promoters. These dual effects augment SREBP1a recruitment and transcriptional activation of lipid synthesis genes. Pharmacological or genetic inhibition of PC, TET1, and SREBP1a, either individually or in combination, effectively suppresses lipid synthesis and tumor growth in vitro and Balb/c nude mouse xenografts. Our findings uncover a PC-TET1-SREBP1a metabolic-epigenetic axis for EOC lipid reprogramming and tumor progression, offering a potential therapeutic target to suppress ovarian cancer aggressiveness.