Synthetic 1,3,6-Tri-O-Galloyl-α-D-Glucose Mimics the Hippo Pathway Inhibitor VT107 in Suppressing Concanavalin...

Glioblastoma (GBM) is the most aggressive primary tumor of the adult central nervous system, not only characterized by rapid proliferation and diffuse brain infiltration but also by a pronounced pro-inflammatory microenvironment that fuels tumor progression and therapeutic resistance. Current standard-of-care, surgical resection followed by radiotherapy and chemotherapy, offers limited survival benefit, partly due to inflammation-driven invasion and immune evasion. The Hippo signaling pathway, a critical regulator of cell proliferation, apoptosis, and tissue homeostasis, has recently been implicated in inflammatory signaling, making it an attractive therapeutic target.

In this study, we investigated the anti-inflammatory and anti-invasive properties of 1,3,6-tri-O-galloyl-α-D-glucose (αTGG), the α-anomer of βTGG from Terminalia chebula, in comparison with pharmacological Hippo pathway inhibitors IAG933, VT107, and GNE7883.

To mimic the inflammatory milieu associated with GBM, U87 cells were treated with Concanavalin A (ConA), which induced phosphorylation of ERK and IκB, key mediators of MAPK and NF-κB inflammatory pathways. Both αTGG and Hippo pathway inhibitors effectively suppressed these phosphorylation events, with VT107 showing the strongest effect. ConA exposure downregulated Hippo pathway downstream effectors (AXL, CTGF, CYR61) in a TEAD-dependent manner, highlighting the interplay between Hippo signaling and inflammatory transcriptional control. Importantly, αTGG and VT107 also significantly attenuated ConA-induced activation of proMMP-2 to MMP-2 and reduced the expression of multiple pro-inflammatory mediators, including COX2, CCL22, CCR2, CCR4, CXCL10, CXCL12, CXCR1, FASLG, IFNG, IL13, and IL17A.

These findings underscore the dual anti-inflammatory and anti-invasive actions of αTGG, positioning it as a promising candidate for targeting inflammation-driven GBM progression through modulation of Hippo pathway activity.