Fraxetin attenuates DNA damage and inflammation in cisplatin-induced nephrotoxicity via FoxO1 activation

Cisplatin-induced acute kidney injury (CKI) represents a severe renal dysfunction characterized by DNA damage and tubular injury. Fraxetin, derived from the Chinese herb Qinpi (Fraxinus bungeana A.DOC), is recognized for its neuroprotective effects and has been used for the prevention of various diseases.

This study investigated the renoprotective effects and molecular mechanisms of fraxetin in CKI. A mouse CKI model and a cisplatin-induced tubule epithelial cell (TEC) injury model were established to evaluate fraxetin's effects by measuring diverse parameters associated with kidney injury, focusing on DNA damage and inflammation. Additionally, network pharmacology and cellular sequencing analysis were employed to identify altered pathways or targets after fraxetin treatment. Subsequent experiments involved siRNA and pharmacological regulation to identify fraxetin targets, alongside molecular docking to unravel binding mechanisms.

Fraxetin pretreatment significantly ameliorated CKI, with a 45% reduction in in tubular damage compared to the cisplatin-only group. Additionally, fraxetin notably enhanced DNA repair. Fraxetin pretreatment reduced cisplatin-induced DNA damage in HK-2 cells by 42.8% in comet assays. Fraxetin also mitigated inflammation, with pro-inflammatory cytokine levels decreasing by approximately 20-30% in both mouse and cell models. Notable changes were observed in the FoxO pathway. Specifically, manipulating Forkhead box O1 (FoxO1), a transcription factor involved in stress responses and longevity, influenced fraxetin's protective effect. Molecular docking revealed that fraxetin binds to the Forkhead (FH) domain of FoxO1, promoting its nuclear localization.

Fraxetin protects against CKI by activating FoxO1, providing a foundation for novel therapeutic strategies and underscoring fraxetin's potential in treating kidney injury.