Honokiol Suppresses Glioma Cell Proliferation by Disrupting SUMO1-YAP1 Conjugation and Promoting YAP1 Proteasomal Degradation.

Among primary central nervous system malignancies in adults, malignant glioma ranks first in incidence, with glioblastoma (GBM) standing as its most aggressive phenotype. This malignancy remains a devastating disease with limited therapeutic options, largely owing to the intricate network of dysregulated signaling pathways. SUMOylation, a post-translational modification that governs thousands of substrate proteins, is markedly hyperactivated in GBM and represents a rational but underexploited target. Here, we found that honokiol (HNK), a natural biphenolic compound extracted from the traditional Chinese medicine Magnolia species, suppressed SUMOylation in glioma cells, with a more prominent reduction in SUMO1-conjugated species than in SUMO2/3-conjugated species. Through a combination of label-free proteomic screening and functional biological assays, we pinpointed YAP1, a core Hippo pathway effector and established oncogenic driver in glioma cells, as a critical downstream target. Furthermore, our research indicated that inhibition of SUMOylation by HNK was associated with reduced levels of YAP1, resulting in glioma cell growth inhibition. Mechanistically, HNK induced YAP1 ubiquitin-proteasome degradation by disrupting SUMO1-YAP1 conjugation, leading to the subsequent blockade of YAP1 signaling. Collectively, our findings unveiled a previously unrecognized mechanism linking pharmacological deSUMOylation to YAP1 destabilization and emphasized the SUMO-YAP1 interface as a therapeutically actionable vulnerability. Overall, this work provides a strong rationale for developing HNK or its optimized derivatives as a first-in-class therapeutic strategy that addresses the network-level complexity of GBM.