Trolline attenuates diabetic vascular injury by regulating SLC7A11-mediated ferroptosis and mitochondrial dysfunction

This study investigated the therapeutic potential of Trolline, a natural compound, for alleviating high-glucose (HG)-induced vascular endothelial ferroptosis and mitochondrial dysfunction via the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) pathway.

In db/db mice, inflammatory damage; glucose tolerance; and the expression of SLC7A11, glutathione peroxidase 4 (GPX4), and long-chain acyl-CoA synthetase family member 4 (ACSL4) were detected after treatment with Trolline. An HG-induced human microvascular endothelial cell (HMEC-1) injury model was established in vitro. Fe²⁺ deposition and GSH levels serve as important indicators of ferroptosis. The mitochondrial membrane potential and the cytoskeleton were determined by JC-1 and F-actin staining, respectively. The levels of apoptosis, cell cycle and reactive oxygen species (ROS) were determined by flow cytometry. Oxidative stress levels were assessed by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Ferroptosis- and inflammation-related protein expression in HMEC-1 cells was verified by Western blotting.

In vivo experiments revealed that Trolline can lower blood sugar levels, alleviate inflammatory damage, and regulate the expression of ferroptosis-related proteins in db/db mice. In vitro experiments demonstrated that Trolline can alleviate various effects induced by HG. Under HG conditions, Trolline can inhibit apoptosis, reverse the cell cycle arrest in the SubG1 phase, reduce oxidative stress levels and Fe²⁺ overload, restore mitochondrial function, promote cytoskeletal remodelling, and regulate the expression of ferroptosis-related proteins. Mechanistically, ferroptosis inhibitors (Ferrostatin-1) and Trolline have the same protective effect on HMEC-1 cells in an HG environment. However, overexpression of SLC7A11 led to loss of the inhibitory effect of Trolline on ferroptosis, which confirms that the effect of Trolline is dependent on the SLC7A11-ferroptosis axis.

Trolline can alleviate diabetic vascular damage through SLC7A11-mediated inhibition of ferroptosis, improved mitochondrial function, and reduced oxidative inflammatory damage, providing a basis for the treatment of diabetic vascular complications.