Specificity Protein 1-induced Taurine Up-regulated Gene 1 promotes vascular injury in diabetic retinopathy via epigenetic silencing of Krüppel-like Factor 2.

The pathogenesis of diabetic retinopathy (DR) is intricately associated with epigenetic regulation, and ferroptosis-mediated retinal vascular injury has been implicated as a potential key factor. However, the precise mechanism underlying epigenetic regulation by the long non-coding RNA taurine up-regulated gene 1 (TUG1) in DR-related vascular injury remains elusive. Initially, clinical samples, including serum and vitreous humor, were collected to examine the relationship between TUG1 and Krüppel-like factor 2 (KLF2). Next, the effects of TUG1 on vascular injury and ferroptosis markers were examined both in vitro and in vivo. Mechanistically, we elucidated the role of the specificity protein 1 (SP1)/TUG1/KLF2 axis. Clinical investigations revealed a negative correlation between TUG1 and KLF2 expression in DR. In a high-glucose environment, the transcription factor SP1 promoted the binding of TUG1 to PRC2, promoting H3K27me3 to suppress KLF2 transcription. This process ultimately led to cell death with the hallmarks of ferroptosis in human retinal microvascular endothelial cells. Functionally, silencing TUG1 or overexpressing KLF2 was shown to alleviate retinal vascular injury and ferroptosis markers in type 2 diabetic mice, and reduce pathological neovascularization in the retinas of OIR mice. Collectively, this study delineates an SP1/TUG1/KLF2 epigenetic axis through which hyperglycemia suppresses KLF2 expression and triggers ferroptosis-like process in retinal microvascular endothelial cells, providing a mechanistic basis for vascular injury in DR.