Introduction: Cognitive impairment is a vital complication of chronic kidney disease (CKD). The effect of irisin on CKD-induced cognitive impairment remains unclear. In the present study, we aimed to investigate the role of Irisin in mitigating cognitive impairment and explore the underlying mechanisms in CKD. Methods: A CKD mice model was established by adenine. Cognitive function was assessed via the novel object recognition (NOR). Interleukin-1β (IL-1β) levels were measured by enzyme-linked immunosorbent assay (ELISA), while pyroptosis-related protein expression was analyzed using western blotting. Results: Our data showed an upregulation of cell pyroptosis in hippocampus tissues of CKD mice, accompanied by significant cognitive impairment. Pyroptosis and cognitive impairment was both improved by Irisin treatment in vivo. Additionally, irisin markedly downregulated pyroptosis levels through aryl hydrocarbon receptor (AhR)/NF-κB p65 signaling in HT-22 cells pretreated with indoxyl sulfate (IS). In vitro experiments further confirmed that pyroptosis was inhibited by AhR and NF-κB p65 inhibitors. Conclusions: We first demonstrated that irisin alleviated cognitive impairment by inhibiting AhR/NF-κB-NLRP3-mediated pyroptosis of hippocampal neurons in CKD. Overall, irisin may have the potential to serve as a critical antipyroptotic agent for improving CKD-induced cognitive impairment.Copyright © 2024 Jialing Zhang et al.