Proteomic analysis reveals the potential mechanism of ergothioneine in preventing acute kidney injury to chronic kidney disease transition.

Acute kidney injury (AKI) is widely recognized as an important risk factor for chronic kidney disease (CKD), and preventing or delaying the AKI-CKD transition represents a critical therapeutic priority. Ergothioneine (EGT), a natural antioxidant, has demonstrated renal protective potential, but its role in attenuating the AKI-CKD transition remains unclear. To investigate this, an AKI-CKD mouse model was constructed by administering multiple small-dose injections of cisplatin. Mice were divided into control, AKI-CKD, and AKI-CKD + EGT groups. The protective function of EGT was assessed using biochemical indexes and histopathology. Proteomic analysis and network pharmacology were applied to identify potential EGT targets, which were further verified by molecular docking and Western blot. Results showed that EGT significantly mitigated renal damage in AKI-CKD mice. Proteomic analysis identified 35 differentially expressed proteins (DEPs) potentially associated with EGT treatment, with GO and KEGG enrichment implicating complement activation as a key pathway. Protein-protein interaction (PPI) network analysis, topology analyses, and molecular docking identified C4B and PON1 as potential core EGT targets. In conclusion, EGT attenuates AKI-CKD progression by targeting C4B and PON1, modulating complement activation and oxidative stress. These findings highlight the therapeutic potential of EGT and provide novel insights for drug development targeting the AKI-CKD transition.