Limonin mitigates cisplatin-induced acute kidney injury through metabolic reprogramming

Xi Zeng; Xianke Zhou; Jiayi Zhou; Hong Zhou; Xue Hong; Dier Li; Yadie Xiang; Menghua Zhong; Yudan Chen; Dongning Liang; Haiyan Fu

doi:10.1016/j.biopha.2023.115531

Limonin mitigates cisplatin-induced acute kidney injury through metabolic reprogramming

Biomed Pharmacother. 2023 Nov:167:115531. doi: 10.1016/j.biopha.2023.115531. Epub 2023 Sep 21.

Authors

Xi Zeng¹, Xianke Zhou¹, Jiayi Zhou¹, Hong Zhou¹, Xue Hong¹, Dier Li¹, Yadie Xiang¹, Menghua Zhong¹, Yudan Chen¹, Dongning Liang¹, Haiyan Fu²

Affiliations

¹ State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
² State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: fuhyan@smu.edu.cn.

PMID: 37741252
DOI: 10.1016/j.biopha.2023.115531

Abstract

Background: Acute kidney injury (AKI) is a known complication of cisplatin administration; currently, there are no effective ways to prevent it. Therefore, it largely limited the use of cisplatin in chemotherapy in the clinic. In this study, we reported that Limonin, a triterpenoid compound extracted from citrus, alleviated cisplatin-induced AKI through metabolic reprogramming in the diseased kidneys.

Methods: Cisplatin was employed to induce AKI in mice. Three groups were set up: Sham, cisplatin + vehicle, and cisplatin + Limonin. Using UHPLC-TOF/MS, we conducted metabolomics to profile the kidneys' endogenous metabolites and metabolic pathways. A network pharmacological method was performed to identify the targets of Limonin on AKI. The human proximal tubular epithelial cell line (HK-2) was applied for in vitro studies.

Results: Limonin preserved serum creatinine and blood urea nitrogen levels after cisplatin-induced AKI. Employing metabolomics, we identified 33 endogenous differentially expressed metabolites and 7 significantly disturbed metabolic pathways in the diseased kidneys within three groups. After AKI, Limonin significantly reduced linoleic acid and its downstream product, arachidonic acid, thus exerting a protective effect on the kidney. The network pharmacological method identified CYP3A4 as a key target of Limonin in treating AKI, while CYP3A4 also serve as a mediator of arachidonic acid metabolism. In vitro, Limonin markedly reduced the level of arachidonic acid and HK-2 cell apoptosis triggered by cisplatin, mainly related to the targeted inhibition of CYP3A4-mediated arachidonic acid metabolism.

Conclusion: Limonin ameliorates cisplatin-induced AKI by inhibiting CYP3A4 activity to regulate arachidonic acid metabolism, ultimately preserving kidney function.

Keywords: Acute kidney injury; Arachidonic acid metabolism; CYP3A4; Cisplatin; Limonin; Metabolomics.