Resveratrol alleviates reactive oxygen species and inflammation in diabetic retinopathy via SIRT1/HMGB1 pathway-mediated ferroptosis

This study aims to explore the potential of using resveratrol (RES) to treat diabetic retinopathy (DR), as well as the involved molecular mechanisms underlying RES-mediated protection against DR. High concentration of glucose (HG)-induced Human retinal capillary endothelial cells (HRCECs) cell model and streptozotocin (STZ)-induced DR mice model were established. Then, cell viability, apoptosis, reactive oxygen species (ROS) levels, pro-inflammatory factors, and expression of the related proteins SIRT1, HMGB1, VEGF, and CD31 were assayed by a series of cell biology methods. Also, the ferroptosis-related indicators were also explored, including contents of Fe²⁺, glutathione (GSH), malondialdehyde (MDA), SLC7A11 and GPX4 protein expression. Results showed that RES could alleviate inflammation and oxidative stress in HG-induced HRCECs. In addition, the mRNA and protein expression of SIRT1 and HMGB1 were significantly changed in HG-induced HRCECs and STZ-induced DR mice, while RES treatment could reverse this alteration. In addition, the HMGB1 acetylation level was enhanced after downregulation of SIRT1. Moreover, the ROS generation, expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α), CD31, and VEGF changed by RES administration were reversed by SIRT1-silence. Besides, HG implement could dramatically up-regulated the Fe²⁺ and MDA contents, and down-regulated the content of GSH and SLC7A11 and GPX4 protein expression in HRCECs, as well as STZ-induced DR mice. RES implement could reverse the above alterations, while SIRT1-silence dramatically reversed these alterations changed by RES treatment. In conclusion, RES suppresses inflammation in DR, as well as inhibit retinal angiogenesis and oxidative stress, and inhibits ferroptosis to alleviate DR via SIRT1/HMGB1 pathway.