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

Ziwei Yuan; Shenlei Yu; Dongyan Su; Yuanyuan Gao; Fan Zheng; Penghua Yan; Xuejia Yang; Zujian Hu; Chaosheng Chen; Hong Lu; Yongheng Bai; Shuibing Cheng

doi:10.1016/j.intimp.2024.114010

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

Int Immunopharmacol. 2025 Jan 6:147:114010. doi: 10.1016/j.intimp.2024.114010. Online ahead of print.

Authors

Ziwei Yuan¹, Shenlei Yu², Dongyan Su³, Yuanyuan Gao², Fan Zheng², Penghua Yan², Xuejia Yang², Zujian Hu², Chaosheng Chen⁴, Hong Lu⁵, Yongheng Bai⁶, Shuibing Cheng⁷

Affiliations

¹ Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Department of Laboratory Medicine, The Third People's Hospital of Ganzhou, Ganzhou 341000, China.
² Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
³ Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
⁴ Department of Nephropathy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Institute of Chronic Nephropathy, Wenzhou Medical University, Wenzhou 325000, China.
⁵ Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: luhonglisa@163.com.
⁶ Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Institute of Chronic Nephropathy, Wenzhou Medical University, Wenzhou 325000, China. Electronic address: wzbyh@wmu.edu.cn.
⁷ Department of Trauma Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: 396289238@qq.com.

PMID: 39765000
DOI: 10.1016/j.intimp.2024.114010

Abstract

Background: 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.

Methods: 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.

Results: 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.

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

Keywords: Acute kidney injury; Cisplatin; DNA damage; FoxO1; Fraxetin; Inflammation.