Astragaloside IV attenuates cisplatin-induced acute kidney injury by suppressing KAT5-mediated NLRP3 acetylation and inflammasome activation.

Cisplatin, a highly effective chemotherapeutic agent, is subject to significant clinical limitations due to its dose-limiting nephrotoxicity, which can result in acute kidney injury (AKI) and chronic kidney disease. The present study investigates the renoprotective potential of Astragaloside IV (AS-IV), a primary bioactive component of Astragalus membranaceus, against cisplatin-induced nephrotoxicity (CIAKI) and elucidates its underlying molecular mechanism. In a murine model, AS-IV treatment was demonstrated to significantly ameliorate cisplatin-induced renal dysfunction, histopathological damage, and the upregulation of markers associated with inflammation and fibrosis. Utilising network pharmacology and molecular docking methodologies, we have identified the pyroptosis pathway as a pivotal target of AS-IV. Subsequent mechanistic studies revealed that AS-IV specifically inhibits NLRP3 inflammasome-mediated pyroptosis. This inhibition occurs via potential binding of AS-IV to the lysine acetyltransferase KAT5 (Tip60), thereby suppressing KAT5 expression and its catalytic activity. Consequently, AS-IV has been demonstrated to impede KAT5-mediated acetylation of NLRP3 at the K24 residue, a critical step for inflammasome assembly and activation. The present study elucidates a hitherto unobserved mechanism by which AS-IV mitigates CIAKI, through the potential targeting of the KAT5/NLRP3 acetylation axis to inhibit pyroptosis. This work provides novel insights into the pathogenesis of cisplatin-induced nephrotoxicity and positions AS-IV as a promising therapeutic candidate for preventing and treating this serious side effect.