TCF7L1 and neoplasm: <i>In vivo</i>, TCF7L1 overexpression, particularly under conditions of enhanced O-GlcNAcylation, significantly suppressed tumor growth and AR expression.<h4>Conclusion</h4>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.