Dihydroartemisinin ameliorates retinal vascular dysfunction in diabetes mellitus via FASN/Kmal-mTOR/SREBP1 feedback loop.

Abstract Microvascular dysfunctions are the primary etiology of visual impairment caused by diabetic retinopathy (DR). Dihydroartemisinin (DHA), the active metabolite of the antimalarials artemisinins, exhibits antiangiogenic properties in numerous diseases. Here, we investigated the function and mechanisms of DHA as a vascular protective agent in DR. DHA exerted its protective effect on vascular injuries in diabetic mice and inhibited cell proliferation and tube formation in human retinal microvascular endothelial cells by decreasing the level of fatty acid synthase (FASN), enhancing the malonylation of mTOR at lysine 1218 (K1218) and attenuating the activation of mTOR complex 1 (mTORC1). Impressively, chemosynthetic small interfering RNA against FASN and mutagenesis of K1218 of mTOR shown therapeutic potential in suppressing cell proliferation and tube formation induced by high glucose. Notably, suppression of mTORC1 kinase activity further inhibited FASN by reducing p70S6K phosphorylation and resulting in reduced expression of sterol regulatory element binding protein 1, which interacted directly with the FASN promoter at nucleotide positions -64 and -55. In conclusion, our study elucidated the promising effect of FASN and malonylation in vascular injuries of DR and indicated the great potential of DHA as a therapeutic approach.