Postoperative cognitive dysfunction (POCD) is common after anesthesia and surgery in older adults, yet no targeted therapy exists, and the mechanism linking volatile anesthetic exposure to circadian dysregulation in the aged hippocampus is undefined. Here we show that RAF manipulation bidirectionally alters CLOCK protein levels in HT22 hippocampal neurons, and that RAF-MAPK-MSK1 protein abundance is inversely related to CLOCK levels in the aged hippocampus after desflurane exposure. Aged C57BL/6 mice (18 months, both sexes) were exposed to 2% desflurane for 2 h, with or without pretreatment with the multi-kinase RAF inhibitor sorafenib (50 mg/kg), and phenotypes were assessed by Western blot, immunofluorescence, in vivo electroencephalography, whole-cell patch-clamp recordings of CA1 pyramidal neurons, and behavioral testing (righting reflex, contextual fear conditioning, Morris water maze). Parallel dissection in HT22 hippocampal neurons employed RAF knockdown, overexpression, and pharmacological inhibition. Desflurane increased total c-Raf, ERK1/2 (MAPK), and MSK1 protein levels-phosphorylation status was not assessed-while reducing CLOCK in both HT22 cells and aged hippocampus, accompanied by cellular senescence, impaired S-phase entry, increased hippocampal β-galactosidase and α-synuclein immunoreactivity, synaptic excitation-inhibition imbalance, and deficits in contextual fear memory and spatial learning. In HT22 cells, RAF knockdown normalized kinase abundance and restored CLOCK, whereas overexpression exacerbated these changes. In aged mice, sorafenib restored CLOCK, attenuated hippocampal β-galactosidase and α-synuclein immunoreactivity, and improved cognitive performance. These findings support a link between RAF-MAPK-MSK1 protein abundance and hippocampal CLOCK in desflurane-induced cognitive impairment and nominate RAF inhibition as a candidate strategy warranting further preclinical study.
