Chiisanogenin Targets MLKL to Restore Autophagy and Suppress Pyroptosis in Renal Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) drives acute kidney injury (AKI) and its progression to chronic kidney disease (CKD), currently lacking effective treatments. This study identifies chiisanogenin, the key bioactive component from Eleutherococcus sessiliflorus fruit extract, as a potent nephroprotective agent. Mechanistically, chiisanogenin targets the mixed lineage kinase domain-like pseudokinase (MLKL)-lysosome axis. It inhibits the pathological translocation of MLKL to the lysosomal membrane, thereby preserving lysosomal integrity. This action promotes the nuclear translocation of transcription factor EB to restore the autophagic flux. Concurrently, it prevents the leakage of cathepsin B into the cytosol, thus suppressing NLRP3 inflammasome activation and subsequent pyroptosis. In vivo and in vitro models confirm that chiisanogenin attenuates IRI-induced acute damage and retards the AKI-to-CKD fibrotic transition. These findings highlight chiisanogenin as a promising therapeutic candidate for treating ischemic renal injury.