Targeting of HSP27 and MMP-2/9 Crosstalk by High-Throughput Drug Repurposing Strategies Identifies Paroxetine as a...

Glioblastoma is the most malignant and treatment-resistant primary brain tumor, driven by extensive cellular plasticity, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling. Heat shock protein 27 (HSP27) stabilizes oncogenic signaling complexes and activates matrix metalloproteinases MMP-2 and MMP-9, facilitating invasion and metastasis. We implemented a structure-based high-throughput screening of FDA-approved compounds to identify inhibitors targeting HSP27-MMP-2/9 crosstalk. In silico studies have identified paroxetine, a selective serotonin reuptake inhibitor, as a high-affinity ligand for HSP27, inducing conformational destabilization and compromising its chaperone activity. Research on LN18 and LN229 glioblastoma cell lines showed that paroxetine treatment decreased cell viability and migration and lowered the levels of HSP27, MMP-2, and MMP-9. The C6 glioma rat model further confirmed the suppression of HSP27 and its crosstalk partner MMP-2/9 in tumor tissue. Collectively, these findings establish paroxetine as a functional HSP27 inhibitor that disrupts the interaction between HSP27 and MMP-2/9, thereby inhibiting glioblastoma progression.