GPT2-mediated Glutamate to α-Ketoglutaric Acid Conversion in Cardiac Fibroblast Promotes Fibrosis

Cardiac fibroblasts play a key role in heart fibrosis, but how their metabolism changes during this process is unclear. This study shows that mesenchymal stem cell-derived extracellular vesicles reduce fibrosis in mice after heart pressure overload. Under stress, fibroblasts increase mitochondrial adenosine triphosphate by boosting glutamate metabolism, especially through the enzyme GPT2, which converts glutamate to α-ketoglutarate. This leads to fibroblast activation and excess collagen. Inhibiting GPT2 via microRNA-30c-5p delivered by mesenchymal stem cell-derived extracellular vesicles -reduces fibrosis in both mice and human cells. GPT2 inhibition also works in other organs, suggesting broad therapeutic potential.