Orientin promotes diabetic wounds healing by suppressing ferroptosis via activation of the <scp>Nrf2/GPX4</scp> pathway

Abstract

Diabetic patients often experience delayed wound healing due to impaired functioning of human umbilical vein endothelial cells (HUVECs) under high glucose (HG) conditions. This is because HG conditions trigger uncontrolled lipid peroxidation, leading to iron-dependent ferroptosis, which is caused by glucolipotoxicity. However, natural flavonoid compound Orientin (Ori) possesses anti-inflammatory bioactive properties and is a promising treatment for a range of diseases. The current study aimed to investigate the function and mechanism of Ori in HG-mediated ferroptosis. A diabetic wound model was established in mice by intraperitoneal injection of streptozotocin (STZ), and HUVECs were cultured under HG to create an in vitro diabetic environment. The results demonstrated that Ori inhibited HG-mediated ferroptosis, reducing levels of malondialdehyde (MDA), lipid peroxidation, and mitochondrial reactive oxygen species (mtROS), while increasing decreased levels of malondialdehyde, lipid peroxidation, and mitochondrial reactive oxygen species, as well as increased levels of glutathione (GSH). Ori treatment also improved the wound expression of glutathione peroxidase 4 (GPX4) and angiogenesis markers, reversing the delayed wound healing caused by diabetes mellitus (DM). Additional investigations into the mechanism revealed that Ori may stimulate the nuclear factor-erythroid 2-related factor 2 (Nrf2)/GPX4 signaling pathway. Silencing Nrf2 in HG-cultured HUVECs negated the beneficial impact mediated by Ori. By stimulating the Nrf2/GPX4 signaling pathway, Ori may expedite diabetic wound healing by decreasing ferroptosis.