Polydatin Attenuates Ferroptosis in Pancreatic β- Cells via Activation of the GPx4-Nrf2 Axis under Hyperglycemic Conditions.

Pancreatic beta cells play a pivotal role in the advancement of type 1 and type 2 diabetes mellitus. Ferroptosis, a distinct type of regulated cell death, is characterized by the accumulation of iron-dependent lipid peroxides in cell membranes, causing disruptions in cellular iron homeostasis and an impaired antioxidant system. Glutathione peroxidase 4 (GPx4) is a key antioxidant enzyme that protects cells against ferroptosis by mitigating oxidative damage and reducing lipid peroxides, thereby maintaining cellular redox balance. In this study, we aim to identify a natural compound as a potent ferroptosis inhibitor using in silico and in vitro approaches. We screened a bioactive compound library using in silico tools and identified polydatin (PD) as a potential GPx4 activator with a strong binding affinity of -7.8 kcal/mol. Its activity was validated using an in-house developed luciferase-based reporter assay system. We further investigated the effects of PD in an in vitro model using mouse pancreatic beta cells exposed to high-glucose conditions. Polydatin exhibited more than 90% cell viability and a dose-dependent protection against ferroptosis and enhanced cellular antioxidant capacity, as evidenced by the upregulation of key ferroptosis-associated markers, including GPx4, solute carrier family 7, ferritin, and transferrin, which were statistically significant. Notably, PD also activated the master antioxidant transcription factor nuclear factor erythroid 2-related factor 2 and its downstream genes, supporting its role in mitigating oxidative stress-induced beta cell dysfunction. Collectively, our findings highlight PD as a promising ferroptosis inhibitor and support its potential as a therapeutic agent for preserving pancreatic beta cell function in diabetes.