@article{Xian2026, 
author = {Peng Xian and Zhenwei Feng and Haitao Yu and Hubin Yin and Haonan Chen and Tenglin Shi and Xilai Li and Chunlin Zhang and Xuesong Bai and Xin Gou and Xinyuan Li and Jie Li},
title = {ONX-0914 Suppresses Hormone-Sensitive Prostate Cancer by Promoting O-GlcNAcylation-Mediated Stabilization of TCF7L1},
year = {2026},
journal = {Oncology Research},
volume = {34},
number = {4},
keywords = {Prostate cancer, transcription factor 7–like 1 (TCF7L1), androgen receptor, O-GlcNAcylation, hexosamine biosynthetic pathway},
url = {https://www.sciopen.com/article/10.32604/or.2026.073156},
doi = {10.32604/or.2026.073156},
abstract = {ObjectiveAndrogen 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.MethodsHSPC 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.ResultsONX-0914 markedly suppressed hormone-sensitive prostate cancer (HSPC) progression through both LMP7-dependent and LMP7-independent mechanisms. Mechanistically, ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation, leading to stabilization of the transcriptional repressor Transcription factor 7–like 1 (TCF7L1) and consequent suppression of androgen receptor (AR) expression. Functionally, activation of the O-GlcNAcylation–TCF7L1 axis inhibited cell proliferation, invasion, migration, and epithelial–mesenchymal transition in vitro. In vivo, TCF7L1 overexpression, particularly under conditions of enhanced O-GlcNAcylation, significantly suppressed tumor growth and AR expression.ConclusionThis 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.}
}