THBS1 and Hyperglycemia: In diabetic conditions characterized by chronic hyperglycemia, high glucose induces TLR9 activation in astrocytes, leading to reactive oxygen species (ROS) generation that impairs thrombospondin-1 (TSP-1) secretion and contributes to synaptic protein loss; both TLR9 deficiency and antioxidant treatment restore TSP-1 levels, implicating TLR9-mediated ROS signaling in metabolic inflammation and synaptic degeneration [133].