HEXB promotes tumor progression of glioblastoma through the HIF1α-CA9 pathway as a therapeutic approach

ABSTRACT: Glioblastoma (GBM) is among the most aggressive and lethal primary malignant brain tumors, notorious for its high recurrence rates. A major challenge in GBM treatment is the paucity of patient-specific therapeutic targets, underscoring the need to identify actionable vulnerabilities that drive GBM progression. Here, through integrative proteomic and transcriptomic profiling of matched GBM tissues and non-tumor tissues adjacent to the tumor from individual patients, we identified the β-subunit of β-hexosaminidase, encoded by HEXB, as a previously underappreciated mediator of GBM progression. Inhibition of HEXB markedly attenuated GBM cell proliferation and tumorigenicity. Mechanistically, HEXB interacted with HIF1α, prevented its ubiquitin-mediated degradation, and promoted its nuclear translocation, thereby enhancing the transcriptional upregulation of CA9, a hypoxia-associated enzyme implicated in glioma progression. Guided by these findings, brain-targeted nanocapsule delivery of HEXB-directed siRNA exerted therapeutic efficacy, as evidenced by robust suppression of GBM cell proliferation and tumor growth, as well as prolonged survival in mice bearing GBM xenografts. This study highlights HEXB as a promising therapeutic target for GBM and supports patient-matched proteotranscriptomic profiling as a feasible strategy for discovering vulnerabilities in GBM precision medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE334976 | GEO | 2026/06/30

REPOSITORIES: GEO