KAT5/8-mediated GPX4 lactylation facilitates ferroptosis and inflammation in diabetic retinopathy

Diabetes-induced hyperglycemia promotes retinal capillary endothelial cell dysfunction, contributing to diabetic retinopathy. In this study, we reveal that high glucose (HG) drives Ferroptosis and inflammation through lactate-mediated GPX4 lactylation. HG conditions enhance glycolysis and lactate production, leading to increased lactylation of GPX4, a process mediated by the acetyltransferases KAT5 and KAT8. GPX4 lactylation reduces its antioxidant function, promoting lipid peroxidation, Ferroptosis, and inflammation. Specifically, HG exposure significantly increases malondialdehyde (MDA) levels, decreases GSH levels, and elevates lipid ROS, while simultaneously inducing pro-inflammatory cytokine expression (IL6, TNF, and IL1B). Inhibition of KAT5 and KAT8 markedly reduces GPX4 lactylation, restores redox balance, suppresses Ferroptosis, and mitigates inflammation. Collectively, our findings identify KAT5- and KAT8-mediated GPX4 lactylation as a key mechanism underlying HG-induced Ferroptosis and inflammation in diabetic retinopathy, highlighting its potential as a promising therapeutic target.

Diabetic retinopathy; Ferroptosis; GPX4; Inflammation; KAT5; KAT8; Lactylation.