Sodium acetate and sodium butyrate ameliorate postoperative cognitive dysfunction in aged rats by suppressing inflammation and ferroptosis via inhibition of the cGAS-STING signaling pathway

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurocognitive complication in elderly patients following surgery. Short-chain fatty acids (SCFAs), including acetate and butyrate, exert anti-inflammatory and antioxidant properties; however, their potential neuroprotective roles in POCD remain largely unexplored. Hence, this study investigated whether sodium acetate (NaA) and sodium butyrate (NaB) ameliorate POCD in aged rats and elucidated the underlying mechanisms. METHODS: A POCD model was established in aged male Sprague-Dawley rats by exploratory laparotomy under isoflurane anesthesia. NaA or NaB was administered orally prior to surgery. Cognitive function was assessed using the Morris water maze (MWM), Y-maze, and novel object recognition (NOR) tests. Hippocampal inflammatory responses were assessed by measuring TNF-α, IL-1β, IL-6, IL-17A, and iNOS levels. Ferroptosis was evaluated by measuring reactive oxygen species (ROS), malondialdehyde (MDA), Fe²⁺ content, antioxidant activities (SOD, GPx, GSH), and the expression of ferroptosis-related genes (TfR1, DMT1, FTH1, FTL, GPX4, and SLC7A11). Activation of the cGAS-STING signaling pathway was examined via Western blot and ELISA. In addition, hippocampal cGAS was overexpressed to assess its causal role. RESULTS: Both NaA and NaB significantly improved cognitive performance in aged POCD rats, as evidenced by enhanced spatial learning and memory in the MWM, increased spontaneous alternation in the Y-maze test, and a higher recognition index in the NOR test. Mechanistically, NaA and NaB markedly suppressed hippocampal inflammation, as evidenced by decreased TNF-α, IL-1β, IL-6, IL-17A, and iNOS levels. NaA and NaB also attenuated ferroptosis, indicated by decreased ROS, MDA, and Fe²⁺ levels, restored SOD, GPx, and GSH activities, upregulated GPX4, SLC7A11, FTH1, and FTL expression, and downregulated TfR1 and DMT1 expression in the hippocampus of aged POCD rats. Furthermore, NaA and NaB inhibited activation of the cGAS-STING signaling pathway in the hippocampus of aged POCD rats. Importantly, hippocampal cGAS overexpression reversed the anti-inflammatory, anti-ferroptotic, and cognitive protective effects of NaA and NaB. CONCLUSION: NaA and NaB ameliorate POCD in aged rats by mitigating hippocampal inflammation and ferroptosis, potentially via inhibition of the cGAS-STING signaling pathway.