TRIM67 Suppresses Glioblastoma Glycolysis and Increases Temozolomide Sensitivity by Promoting ARSD Ubiquitinated Degradation to Inactivate the β-Catenin Pathway.

Glioblastoma (GBM) is one of the deadliest malignant tumors in the central nervous system. Temozolomide (TMZ) resistance is a crucial cause of treatment failure in GBM. We intended to explore the molecular mechanisms by which ARSD modulated TMZ resistance in GBM. This study revealed that ARSD was up-regulated in GBM and associated with GBM recurrence and poor prognosis. Furthermore, knockdown of ARSD suppressed glycolysis and increased TMZ sensitivity in GBM cells. Mechanistic insights demonstrated that TRIM67 promoted the ubiquitinated degradation of ARSD through the RING structural domain. Concurrently, overexpression of TRIM67 repressed GBM cell glycolysis and increased sensitivity to TMZ by decreasing ARSD expression. Additionally, TRIM67 down-regulated ARSD to hinder β-catenin-mediated glycolysis in GBM cells and suppressed tumor growth in nude mice. Taken together, TRIM67 suppresses ARSD expression by facilitating its ubiquitin-mediated degradation, thereby inactivating the β-catenin pathway to repress GBM glycolysis and TMZ resistance. This study reveals the TRIM67/ARSD/β-catenin axis as a key regulator of GBM metabolic reprogramming and TMZ resistance, offering a novel therapeutic target.