Abstract
Hinokitiol is a natural bioactive tropolone derivative isolated from Chamaecyparis obtusa and Thuja plicata, which exhibits promising potential in terms of antioxidant and anti-inflammatory properties and possesses potent iron-binding capacity. In this study, we aimed to investigate the potential role of hinokitiol in protecting against ethanol-induced gastric injury and elucidate the underlying mechanism. Our results demonstrated that hinokitiol effectively attenuated hemorrhagic gastric lesions, epithelial cell loss, and inflammatory response in mice with ethanol-induced gastric injury. Intriguingly, we found that ethanol exposure affects iron levels both in vivo and in vitro. Moreover, the disturbed iron homeostasis was involved in the development of ethanol-induced injury. Iron depletion was found to enhance defense against ethanol-induced damage, while iron repletion showed the opposite effect. To further explore the role of iron sequestration in the protective effects of hinokitiol, we synthesized methylhinokitiol, a compound that shields the iron binding capacity of hinokitiol with a methyl group. Interestingly, this compound significantly diminishes the protective effect against ethanol-induced injury. These findings collectively demonstrated that hinokitiol could potentially be used to prevent or improve gastric injury induced by ethanol through regulating cellular iron homeostasis.