BCAT1 activation reprograms branched-chain amino acids (BCAAs) metabolism and epigenetically promotes inflammation in diabetic retinopathy

Branched-chain amino acids (BCAAs) metabolism is dysregulated in diabetic retinopathy. Retina Müller cells maintain various metabolic processes and immune homeostasis. Here, we found that branched-chain aminotransferase 1 (BCAT1), which catalyzes the first step of BCAAs metabolism, was predominantly expressed in retina Müller cells. Under diabetic conditions, BCAT1 showed increased enzymatic activity in Müller cells, which drove the remodeling of BCAAs catabolism, and upregulated the expression of inflammatory genes such as interleukin 6 (IL6) and tumor necrosis factor-α (TNF-α). Mechanistically, BCAT1 activity was negatively regulated by Polo-like kinase 4 (PLK4) via phosphorylation at threonine 333. Increased BCAT1 activity further reduced α-ketoglutarate (α-KG) levels, a critical substrate for histone demethylation, resulting in higher H3K4me3 levels at inflammatory gene promoters, and further upregulated inflammation genes. Treatment with chemical BCAT inhibitor significantly reduced inflammatory gene expression and vascular leakage in diabetic retinas in vivo. These findings reveal a crucial role of BCAT1 in metabolic remodeling and inflammatory regulation, which indicates that BCAT1 could be used as a target for diabetic retinopathy.