<p>This study aims to evaluate the protective effect of buspirone (BUS) against liver damage caused by cyclophosphamide (CPA) by focusing on the α-klotho/Nrf2/HO-1 and AMPK/NF-κB p65/NLRP3/caspase-1 signaling cascades. The possible damage that CPA might produce was evaluated using histological examination in conjunction with serum AST, ALT, and direct bilirubin. GSH and MDA levels were measured using a colorimetric technique. TNF-α, IL-1β, and IL-18 levels, as well as hepatic caspase-1, hepatic p-AMPK, and serum α-klotho, were measured using the ELISA technique. Using an immunohistochemistry method, the Nrf2 and caspase-3 expression in the liver tissue was investigated. The expression of HO-1 mRNA was assessed by means of RT-qPCR. The expression levels of NF-κB p65 and NLRP3 were assessed by western blotting. BUS, in a dose-dependent manner, attenuated CPA-induced hepatotoxicity by reducing the elevated serum AST, ALT, and direct bilirubin and alleviating the histopathological aberrations. Additionally, it raised GSH levels and decreased MDA levels. In addition, it reduced levels of inflammatory markers and caspase-3 expression. BUS also increased p-AMPK and α-klotho protein levels and stimulated the production of Nrf2 and HO-1. Additionally, it reduced pyroptosis by downregulating NLRP3 and caspase-1 expression levels. BUS attenuated NF-κB p65/NLRP3 inflammasome and caspase-3-mediated apoptotic activity and enhanced Nrf2/HO-1 activity, therefore mitigating the liver impairment provoked by CPA.</p>