Targeting DOT1L-mediated histone methylation by hesperetin alleviates retinal microvascular endothelial cell dysfunction and diabetic retinopathy.

The role of disruptor of telomeric silencing-1 like (DOT1L) mediated histone methylation in the pathophysiology of diabetic retinopathy (DR) and retinal microvascular endothelial (RME) cell dysfunction remains inadequately elucidated. In this study, we demonstrate that the attenuation of RME cell dysfunction was observed upon either knockdown or inhibition of DOT1L, which was correlated with a downregulation of fatty acid synthase (FASN) and sterol regulatory element-binding protein 1 (SREBF1) expression through histone methylation-dependent mechanisms. Furthermore, targeted knockdown of DOT1L was found to alleviate the progression of DR in diabetic murine models. Importantly, the flavonoid hesperetin (Hes) demonstrated the ability to directly interact with DOT1L, thereby inhibiting its enzymatic activity, which in turn ameliorated RME cell dysfunction and decreased FASN and SREBF1 expression via histone methylation mechanisms. These findings not only position DOT1L as a novel therapeutic target for intervention in DR but also identify Hes as a promising lead compound for future DR therapeutic strategies.