CISD2 ameliorates heatstroke-associated early cognitive deficits by inhibiting ferroptosis and maintaining dendritic spine density in hippocampal neurons in mice

Heatstroke encephalopathy is a universal primary manifestation of heatstroke. Early brain injury caused by heatstroke may lead to long-term cognitive impairment in survivors, yet it frequently evades detection by standard diagnostic techniques. Thus, the discovery of reliable biomarkers for early brain injury detection is necessary. In this study, CISD2 downregulation in HT-22 cells was observed following hyperthermia treatment by using transcriptomics analysis. Subsequent mechanistic investigations revealed that CISD2 downregulation triggeres ferroptosis via AMPK-dependent BECN1 phosphorylation at Ser93, while CISD2 overexpression confers ferroptosis resistance in HT-22 cells at 41 °C. Furthermore, the downregulation of CISD2 expression and ferroptotic alterations were firmly observed in hippocampal tissues of mice during the early stage of heatstroke, and the overexpression of CISD2 by injecting lentivirus overexpressing CISD2 into the hippocampus of mice significantly alleviated heatstroke-induced neuronal loss, and meanwhile, the density of dendritic spines in the CA1 pyramidal neurons of the mice was effectively preserved. Moreover, knockdown of the CISD2 in the hippocampus exacerbated the loss of hippocampal neurons and the reduction of dendritic spine density. In summary, our results illustrated that CISD2 plays a pivotal role in preserving normal hippocampal function by regulating lipid peroxidation and iron homeostasis of heatstroke conditions. These finds provide novel insights into the mechanisms underlying heatstroke-induced cognitive deficits and offer potential strategies for improving risk prediction of heatstroke encephalopathy.