Hinokitiol functions as a ferroptosis inhibitor to confer neuroprotection

The intrinsic link of ferroptosis to neurodegeneration, such as Parkinson's disease and Alzheimer's disease, has set promises to apply ferroptosis inhibitors for treatment of neurodegenerative disorders. Herein, we report that the natural small molecule hinokitiol (Hino) functions as a potent ferroptosis inhibitor to rescue neuronal damages in vitro and in vivo. The action mechanisms of Hino involve chelating irons and activating cytoprotective transcription factor Nrf2 to upregulate the antioxidant genes including solute carrier family 7 member 11, glutathione peroxidase 4 and Heme oxygenase-1. In vivo studies demonstrate that Hino rescues the deficits of locomotor activity and neurodevelopment in zebrafishes. In addition, Hino shows the efficient blood-brain barrier permeability in mice, supporting the application of Hino for brain disorders. Paclitaxel is one of the most widely used broad-spectrum antineoplastic agents. However, its neurotoxic side effect is a severe concern. We demonstrate that the neurotoxicity of paclitaxel is ferroptosis-related and Hino also alleviates the paclitaxel-induced neurotoxicity without compromising its cytotoxicity to cancer cells. Hino also salvages the neurobehavioral impairment by paclitaxel in zebrafishes. Collectively, the discovery of Hino as a novel ferroptosis inhibitor and disclosure of its action mechanisms establish a foundation for the further development of Hino as a neuroprotective agent.