YAP1 aggravates hyperglycemia-induced retinal capillary endothelial cells injury via ferroptosis and inflammation regulation

Diabetic retinopathy (DR) is a severe vascular complication that causes blindness. Retinal capillary endothelial cells are the primary targets of DR, with ferroptosis and inflammation playing critical roles. YAP1, a downstream effector of the Hippo pathway, was recently shown to regulate ferroptosis and inflammation; however, its mechanisms in DR is not fully understood. Herein, we investigated the role of YAP1 in ferroptosis and inflammation in DR and hyperglycemia-induced human retinal capillary endothelial cells (HRCECs). The expression levels, including markers of ferroptosis and inflammation, and the nuclear localization of YAP1 were increased in diabetic retinal tissues and high glucose-treated HRCECs. YAP1 regulated ferroptosis and inflammation in vitro. Moreover, silencing YAP1 inhibited the high glucose-induced elevation of ACSL4, TFRC, IL-6, and TNF-α levels and the decline in GPX4 levels in HRCECs, protecting them from ferroptosis, inflammation, and oxidative stress. Conversely, YAP1 overexpression had the opposite effect. Additionally, under high glucose conditions, the ferroptosis inducer RSL3 diminished the protective effects of YAP1 silencing, while the ferroptosis inhibitor ferrostatin-1 rescued HRCECs from YAP1 overexpression-induced injury. Collectively, our results demonstrate that YAP1 is involved in DR development and mediates ferroptosis and inflammation in HRCECs under high glucose environments, providing a potential therapeutic target in DR.