ONX-0914 Suppresses Hormone-Sensitive Prostate Cancer by Promoting O-GlcNAcylation-Mediated Stabilization of TCF7L1

Objective: Androgen receptor (AR) signaling is a central driver of prostate cancer progression, yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized. This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer (HSPC) through metabolic modulation of AR and aimed to identify the transcriptional mediator involved. Methods: HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation, invasion, migration, and epithelial-mesenchymal transition. Xenograft assays, bioinformatic screening, and analyses of O-GlcNAcylation and protein stability were performed, together with quantitative polymerase chain reaction (qPCR) and Western blotting. Results: , TCF7L1 overexpression, particularly under conditions of enhanced O-GlcNAcylation, significantly suppressed tumor growth and AR expression. Conclusion: This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1, leading to repression of AR signaling and inhibition of HSPC progression. These findings reveal a previously unrecognized metabolic-transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.