ATRX Loss Upregulates UGDH via Chromatin Remodeling to Promote SOX2 m6A Modification and Stemness Maintenance in Glioblastoma

<title>Abstract</title> <p> UDP-glucose 6-dehydrogenase (UGDH) catalyzes the conversion of UDP-glucose (UDP-Glc) to UDP-glucuronic acid (UDP-GlcUA) and is implicated in tumor progression. However, the mechanisms governing UGDH expression and its potential feedback regulation in glioma stem cell (GSC) maintenance remain unclear. Here, we demonstrate that ATRX loss-induced chromatin remodeling drives UGDH upregulation, which in turn promotes malignant properties and stem-like characteristics in GSCs. Mechanistically, elevated UGDH depletes intracellular UDP-Glc, relieving its inhibition of VIRMA, a core component of the m ⁶ A methyltransferase complex. Consequently, VIRMA binds more efficiently to SOX2 mRNA, promoting its m ⁶ A modification and stabilization. Collectively, our findings establish UGDH as a critical regulator of GSC stemness and highlight its potential as a therapeutic target in glioblastoma through epigenetic modulation. Pharmacological inhibition of UGDH by the small-molecule inhibitor HY-155534 effectively suppressed GSC stemness and tumor growth <italic>in vivo</italic> . </p>