DHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells.

DHODH inhibition, not KDM4 suppression, underpins the antiproliferative effects of QC6352 and zavondemstat in glioblastoma models, with DHODH as the key target.

• Why it matters: Understanding the true mechanism of these compounds is crucial for developing effective glioblastoma therapies, as previous assumptions about KDM4 targeting may be misleading.
• What they did: Researchers used chemical biology approaches in glioblastoma models to show that the antiproliferative activity of QC6352 and zavondemstat depends on DHODH inhibition, not KDM4 inhibition, with uridine supplementation and resistant mutants confirming this.
• The result: This work reveals that DHODH inhibition drives the antitumor activity of these compounds, emphasizing the importance of accurate target identification and the use of orthogonal probes in drug mechanism studies.