ZNF280A and ACRV1 enhance aerobic glycolysis and drive ovarian cancer progression via the PI3K/AKT signaling pathway.

Ovarian cancer (OC) remains a leading cause of gynecological cancer-related mortality, largely due to metabolic reprogramming and aggressive progression. Zinc finger protein 280A (ZNF280A), a poorly characterized transcriptional regulator, has recently been implicated in tumorigenesis, but its mechanistic role in OC remains undefined. Here, we identify ZNF280A as an oncogenic driver that promotes OC progression through transcriptional regulation of acrosomal vesicle protein 1 (ACRV1) and activation of the PI3K/AKT signaling pathway. ZNF280A expression was markedly elevated in OC tissues and cell lines and correlated with advanced clinicopathologic features and poor patient survival. Functional assays revealed that ZNF280A knockdown inhibited OC cell proliferation, migration, and tumorigenesis while inducing apoptosis both in vitro and in vivo. Mechanistically, ZNF280A enhanced ACRV1 transcription by interacting with the transcription factor CUX2, thereby facilitating its recruitment to the ACRV1 promoter. Elevated ZNF280A or ACRV1 expression activated PI3K/AKT signaling and increased glycolytic enzyme expression (PKM2 and LDHA), glucose uptake, lactate production, ATP generation, and extracellular acidification rate, whereas pharmacological inhibition of AKT or glycolysis abrogated these effects. Collectively, our findings establish ZNF280A as a key regulator of metabolic reprogramming in OC through the CUX2-ACRV1-PI3K/AKT axis, highlighting this pathway as a potential therapeutic target in ovarian cancer.