Ver E's structure was validated by (1)H NMR, HRMS, and molecular networking analyses. Computational docking and NMR titration confirmed direct, saturable, and tight binding of Ver E to the human Sigma-2 receptor/transmembrane protein 97 (σ(2)R/TMEM97). Functional calcium imaging in primary mouse sensory neurons revealed that Ver E increases intracellular Ca(2+) levels without modulating store-operated calcium entry (SOCE). Multi-well microelectrode array experiments using human induced pluripotent stem cell (hiPSC) derived nociceptors showed that Ver E significantly reduced neuronal activity at physiological temperatures, but not under heat-stress conditions. Ver E exhibited no cytotoxicity at concentrations up to 30 μM in HEK293 cells, and immunocytochemistry confirmed that it does not alter phosphorylated eIF2α (p-eIF2α) expression, indicating a mechanism distinct from integrated stress response modulators. Collectively, these findings position Ver E as a non-toxic compound capable of selectively modulating neuronal excitability, thereby advancing the development of novel therapeutics for pain management.