Fumarate hydratase suppresses glioblastoma progression by restricting fumarate-mediated succination of TRIM17.

Emerging evidence indicates that metabolic reprogramming plays a pivotal role in glioblastoma (GBM) progression. Here, we report that the expression of fumarate hydratase (FH) is significantly reduced in GBM patient samples. FH overexpression suppresses the viability, migration, and invasion of GBM cells, whereas FH knockdown or pharmacological inhibition produces the opposite effects. Consistent with FH downregulation, its substrate fumarate accumulates in GBM cells and clinical tumor tissues. As a result, excess fumarate induces succination of TRIM17 at Cys370, thereby reducing TRIM17 protein stability and impairing its E3 ubiquitin ligase activity. Subsequent functional studies identify TRIM17 as a tumor suppressor in GBM. In vivo xenograft models further confirm that FH restrains GBM progression by regulating TRIM17 succination. Collectively, these findings establish FH as a negative regulator of GBM and reveal a fumarate-TRIM17 signaling axis that promotes GBM malignancy through post-translational modification of TRIM17.