UCA1 facilitates endometriosis progression through EIF4A3-mediated stabilization of E2F1 mRNA and enhanced glycolysis

Long non-coding RNA Urothelial carcinoma-associated 1 (UCA1) is a pivotal regulator in the progression of endometriosis (EMs), yet its mechanistic role remains elusive. This study identified UCA1 as a factor promoting glycolysis through bioinformatic screening and functional validation. Ectopic endometrial lesions exhibited significant UCA1 upregulation compared to normal endometrial tissues. In ectopic endometrial stromal cells, UCA1 knockdown suppressed glycolytic activity, evidenced by diminished glucose uptake and lactate production, while rescue experiments demonstrated that overexpression of E2F Transcription Factor 1 (E2F1) reversed this metabolic suppression. Mechanistically, UCA1 recruited eukaryotic translation initiation factor 4A3 (EIF4A3) to stabilize E2F1 mRNA, establishing an RNA-protein complex confirmed by RNA immunoprecipitation, RNA pull-down, and fluorescence in situ hybridization assays. Further experiments have demonstrated that EIF4A3 directly targets the 3'-untranslated region (UTR) of E2F1. Chromatin immunoprecipitation assays demonstrated that E2F1 binds to the promoter of pyruvate kinase isozyme type M2 (PKM2), thereby activating its transcription and linking UCA1-mediated E2F1 regulation to glycolytic reprogramming. In vivo validation using a subcutaneous xenograft model indicated that silencing UCA1 significantly inhibited the growth of endometriotic lesions. These findings support a UCA1/EIF4A3/E2F1/PKM2 regulatory axis that drives EMs progression through metabolic alterations. This study provides evidence for UCA1 as both a disease-promoting effector and a valuable therapeutic target, with implications for developing diagnostic and treatment strategies that target lncRNA-mediated metabolic dysregulation in EMs.