DGAT1-associated lipid-retinoid dysregulation correlates with metabolic impairment in the RPE of Stargardt disease

Mutations in ABCA4 cause Stargardt disease (STGD1) by disrupting retinoid handling and retinal pigment epithelium (RPE) homeostasis, yet the metabolic drivers of RPE degeneration remain unclear. Given that photoreceptor health relies heavily on the support of the RPE, loss of the RPE cells is central to STGD1 pathology. In this study, we show that dysregulation of diacylglycerol O-acyltransferase-1 (DGAT1) is associated with disrupted retinoid-lipid metabolism in STGD1 RPE cells, accompanied by excess retinyl esters and neutral lipid accumulation, impaired lipid processing, and reduced mitochondrial activity. These findings implicate DGAT1-mediated lipid remodeling as a contributing factor to RPE dysfunction in ABCA4 -associated retinopathies.