Resveratrol mitigated acute sleep deprivation-induced cognitive impairment by suppressing hippocampal neuronal ferroptosis.

Sleep deprivation (SD) induces extensive neuropsychiatric disorders, including cognitive impairment, which reduce the life quality of the victim and increase the burden on the healthcare system. The potential underlying mechanism and promising preventions for sleep deprivation-induced cognitive impairment remain to be further explored. Our preliminary study found that sleep deprivation activated ferroptosis in mice hippocampi. Hence, we set out to examine the potential interaction between ferroptosis and STING. Interestingly, we found that mice model of acute sleep deprivation (ASD) for 72 h displayed cognitive impairment in Y-maze and novel object recognition test. Accordingly, ASD increased ferroptosis revealed by decreased levels of Glutathione peroxidase 4 (GPX4), ferritin (FTH), solute Carrier Family 7 Member 11(xCT) and increased levels of transferrin receptor(TFRC) in the hippocampi. Surprisingly, we observed remarkably decreased hippocampal levels of STING, p-TANK-binding kinase-1 (p-TBK1), and p-interferon regulatory factor-3 (p-IRF3), which were colocalized with Iba1 in ASD mice. Notably, resveratrol pretreatment suppressed ASD-induced ferroptosis and increased the expression of STING/TBK1/IRF3 signaling pathway in the hippocampi, and then mitigated cognitive dysfunction of ASD mice in behavioral tests. However, STING inhibitor H-151 significantly weakened the neuroprotective effects of resveratrol. Based on these findings, it was indicated ferroptosis interacted with STING signaling possibly at GPX4 and then reduced the activity of STING signaling, and finally disturbed the balance of microglia. Furthermore, resveratrol is held as a promising neuroprotective compound to prevent ASD-triggered cognitive impairment by modulating hippocampal ferroptosis and STING signaling.