Ginkgolide B alleviates diabetic retinopathy by inhibiting ferroptosis in retinal vascular endothelial cells via the TSPO/Nrf2 pathway

Ginkgolide B (GB) protects against diabetes complications, yet its role in diabetic retinopathy (DR) and the underlying mechanisms remain poorly understood. This study aims to elucidate the therapeutic mechanisms of GB in DR. A high-fat diet (HFD) combined with streptozotocin (STZ)-induced diabetic mouse model and a high-glucose-treated human retinal microvascular endothelial cell (hRMEC) model were used to explore the effects of GB on diabetes-induced retinal dysfunction. Both of them were treated with GB or the Ferroptosis inhibitor ferrostatin-1 (Fer-1). Our in vitro and in vivo experiments demonstrated that glucolipotoxicity impairs vascular endothelial function and elevates Ferroptosis levels. GB treatment improved retinal thickness and vascular barrier function in DR mice by suppressing Ferroptosis. Furthermore, GB treatment improved hRMECs cell viability, proliferation, migration, and tube formation activity also by attenuating Ferroptosis. Utilizing a network pharmacology (NP) approach, we identified translocator protein (TSPO) as a key target of GB in protection of DR, inhibition of TSPO markedly abolished the therapeutic benefits of GB in DR. Mechanistically, glucolipotoxicity suppressed the TSPO/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway, whereas GB treatment restored its activity, ultimately leading to the inhibition of Ferroptosis. GB protects cells and tissues from glucolipotoxicity in DR models by inhibiting Ferroptosis through promoting TSPO/Nrf2 signaling. Administration of GB in diabetic patients may delay the onset of retinopathy or alleviate the progression of diabetic retinopathy.

Diabetic retinopathy; Endothelial cells; Ferroptosis; Ginkgolide B; Nrf2; TSPO.