*4.5. Salicin*

Salicin is the main component of the willow bark extract, commonly used in traditional medicine for its anti-inflammatory and antipyretic e ffects [115]. Salicin is metabolized to salicylic acid in vivo; therefore, it is also known as "nature's aspirin". Previous studies showed that salicin exerts protective effects on EC, both inhibiting angiogenesis [116] and reducing ROS production [117]. Song et al. demonstrated that the treatment of HRECs with salicin led to a reduction in HMGB1 release and the prevention of cellular apoptosis. Moreover, the authors demonstrated that salicin can suppress the production of IL-1β and its related cytokines, such as TNF-κ and IL-6, responsible for retinal toxicity. Salicin is also able to block the release of the adhesion molecules ICAM-1 and VCAM-1 and the NF-κB inflammatory pathway [118].

#### *4.6. Ethyl Pyruvate (EP)*

Ethyl pyruvate is a pyruvate derivative with the addition of an aliphatic ester group. EP is considered to be safer and more e ffective than pyruvate in inhibiting ROS and inflammation [119]. EP is a strong HMGB1 inhibitor. Treatment with EP promotes stable vascular growth and blocks retinal pathological neovascularization by preventing the overexpression of HMGB1. Moreover, EP can inhibit the expression of IL-6, TNF-<sup>κ</sup>, and NF-kB, exerting a protective role in chronic inflammatory diseases such as DR [120].
