Gastrodin attenuates high fructose-induced sweet taste preference decrease by inhibiting hippocampal neural stem cell ferroptosis.

INTRODUCTION: High fructose intake has been implicated as a risk factor for behavioral disorders, potentially through cell ferroptosis induction in the central nervous system. Neural stem cells (NSCs) are crucial for maintaining hippocampal neurogenesis to resist behavioral alterations. Gastrodin, derived from the traditional Chinese herb Gastrodia elata, has neuroprotective effect. OBJECTIVES: This study aimed to elucidate the underlying mechanism by which high fructose induces sweet taste preference and assesses the impact of gastrodin on hippocampal NSC ferroptosis. METHODS: Mice and cultured NSCs were treated with high fructose and/or gastrodin, respectively. NSC ferroptosis was evaluated by assay of lipid peroxidation and DNA double-strand breaks. Transcriptome sequencing (RNA-seq), Western blotting, and chromatin immunoprecipitation (ChIP) were employed to explore the potential mechanism underlying high fructose-induced NSC ferroptosis and the modulation of gastrodin. Simultaneously, specific gene expression was regulated by lentivirus injection into the hippocampus of mice. RESULTS: Our data showed that gastrodin mitigated sweet taste preference decline and hippocampal NSC ferroptosis in high fructose-fed mice, being consistent with reduction of reactive oxygen species (ROS) and iron accumulation in hippocampal NSC mitochondria. Mechanistically, we identified CDGSH iron-sulfur domain 1 (CISD1) as a mediator of NSC ferroptosis, with its expression being augmented by high fructose. Overexpression of Zic family member 2 (ZIC2) increased the transcription of Cisd1 gene. Additionally, overexpression of Zic2 with lentiviral vectors in hippocampus showed the decreased sweet taste preference in mice, consistently up-regulated CISD1 protein expression and reduced hippocampal NSC number. Gastrodin downregulated ZIC2 expression to inhibit CISD1 transcription in its attenuation of high fructose-induced NSC ferroptosis and sweet taste preference decrease. CONCLUSION: Collectively, high fructose can drive hippocampal NSC ferroptosis by upregulating ZIC2 and CISD1 expression, thereby contributing to the decline in sweet taste preference. Gastrodin emerges as a promising agent for mitigating NSC ferroptosis and improving sweet taste preference.