FPGS drives breast cancer proliferation via CDK9-mediated mitophagy through the mTOR signaling pathway.

Breast cancer remains the leading cause of cancer death among women worldwide, and metabolic reprogramming is increasingly recognized as a hallmark of this disease. Folylpolyglutamate Synthase (FPGS), a key enzyme in folate metabolism, catalyzes the polyglutamylation that retains folate inside cells; however, its role in breast cancer tumorigenesis remains largely unknown. Here, we show that FPGS is markedly upregulated in breast cancer tissues and that high FPGS expression is associated with poor patient survival. FPGS drives breast cancer cell proliferation in vitro and tumor growth in vivo by enhancing mitophagy, an effect mediated through suppression of the mTOR signaling pathway. Mechanistically, FPGS interacts with Cyclin-dependent kinase 9 (CDK9) and stabilizes it by deubiquitination, which in turn sustains mitophagy and promotes tumor progression. Pharmacological inhibition of CDK9 or mitophagy abolishes FPGS-driven proliferation, while CDK9 inhibitor treatment suppresses tumor growth in vivo. These findings identify the FPGS-CDK9-mTOR axis as a critical regulator of mitophagy and breast cancer progression, highlighting FPGS as both a candidate diagnostic biomarker and a potential therapeutic target for breast cancer.