@Article{or.2026.073156,
AUTHOR = {Peng Xian, Zhenwei Feng, Haitao Yu, Hubin Yin, Haonan Chen, Tenglin Shi, Xilai Li, Chunlin Zhang, Xuesong Bai, Xin Gou, Xinyuan Li, Jie Li},
TITLE = {ONX-0914 Suppresses Hormone-Sensitive Prostate Cancer by Promoting O-GlcNAcylation-Mediated Stabilization of TCF7L1},
JOURNAL = {Oncology Research},
VOLUME = {34},
YEAR = {2026},
NUMBER = {4},
PAGES = {--},
URL = {http://www.techscience.com/or/v34n4/66680},
ISSN = {1555-3906},
ABSTRACT = { <b>Objective:</b> 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. <b>Methods:</b> 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. <b>Results:</b> ONX-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 <i>in vitro</i>. <i>In vivo</i>, TCF7L1 overexpression, particularly under conditions of enhanced O-GlcNAcylation, significantly suppressed tumor growth and AR expression. <b>Conclusion:</b> 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.},
DOI = {10.32604/or.2026.073156}
}