Glycolytic reprogramming and the EMT drive cervical cancer progression via the NQO1/HIF1α-SIX1 axis

Abstract

Cervical cancer aggressiveness and therapeutic resistance are driven by metabolic reprogramming and redox imbalance. Within this context, NAD(P)H: quinone oxidoreductase 1 (NQO1), a critical regulator of cellular redox homeostasis and energy metabolism, is highly expressed in several types of cancer and is associated with poor prognosis; however, its role in cervical cancer remains unclear. This study demonstrates that NQO1 is significantly upregulated in cervical cancer, promoting proliferation, metastasis, and epithelial-mesenchymal transition (EMT). Mechanistically, NQO1 suppresses AMP-activated protein kinase (AMPK) phosphorylation to reduce reactive oxygen species (ROS), while stabilizing HIF1α by preventing its proteasomal degradation. Consequently, stabilized HIF1α upregulates sine oculis homeobox 1 (SIX1) to enhance glycolytic enzyme transcription, driving aerobic glycolysis. Functional rescue experiments demonstrated that knockdown of NQO1, HIF1α, or SIX1 significantly inhibited glycolytic flux, tumor growth, and metastasis in vivo . Thus, the NQO1/HIF1α-SIX1 axis orchestrates metabolic reprogramming and EMT to promote cervical cancer progression and is a promising therapeutic target.