Open Access

ARTICLE

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

Peng Xian^1,2,#, Zhenwei Feng^1,3,#, Haitao Yu³, Hubin Yin^1,3, Haonan Chen¹, Tenglin Shi¹, Xilai Li^1,3, Chunlin Zhang^1,3, Xuesong Bai^1,3, Xin Gou^1,*, Xinyuan Li^1,3,*, Jie Li^1,*

1 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
2 Department of Urological Oncology, Chongqing University Cancer Hospital, Chongqing, China
3 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China

* Corresponding Authors: Xin Gou. Email: ; Xinyuan Li. Email: ; Jie Li. Email:
# These authors contributed equally to this work as the first author

(This article belongs to the Special Issue: Molecular Mechanisms of Urogenital Cancers)

Oncology Research 2026, 34(4), 31 https://doi.org/10.32604/or.2026.073156

Received 11 September 2025; Accepted 09 February 2026; Issue published 23 March 2026

Abstract

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: 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 in vitro. In vivo, 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.

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Supplementary Material

Supplementary Material File

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