SUN-544 Yes Associated Protein Inhibitor Verteporfin Protects Against Streptozotocin-induced Insulin Dysfunction and Damage Responses by Blocking S1PR2,ERK and p65 Signaling Cascade

Abstract Disclosure: K. Jang: None. J. Moon: None. J. Park: None. Insulin-secreting β cells in the pancreatic islets are exposed to various endogenous and exogenous stressing conditions, which may lead to β-cell dysfunction or apoptosis and ultimately to diabetes mellitus. Sphingosine 1-phosphate (S1P) regulates insulin resistance and pancreatic β-cell destruction via the sphingosine-1-phosphate receptor (S1PR)2-mediated pathway. Activation of S1PR2-Yes-associated protein (YAP) plays an important role in cell proliferation, apoptosis, migration, differentiation, and invasion. Verteporfin (VP), a YAP inhibitor, has been approved for use with photodynamic therapy to treat age-related macular degeneration. We investigated the protective effects of VP against streptozotocin (STZ)-induced insulin dysfunction and cell death mediated via S1PR2 signaling. Considering the VP-mediated molecular mechanism that protects the cells against apoptotic responses, VP potently inhibits STZ-induced mitochondrial membrane potential and cleaved-poly polymerase (PARP) expression. VP reduced STZ-induced oxidative and ER stress as verified using inhibitors. In STZ-stimulated cells, VP robustly inhibited MAPK-extracellular signal-regulated kinase (ERK) phosphorylation and NFκB-p65 translocation. The correlation between MAPK-ERK and p65 in cell death responses were verified using suitable inhibitors. VP can restore STZ-induced suppression of insulin expression to normal levels. The accumulated literature and our findings suggest that VP is a promising candidate for insulin dysfunction and cell death responses, and could be employed in various pathological conditions, including diabetes. Presentation: Sunday, July 13, 2025