Aurantiamide mitigates acute kidney injury by suppressing renal necroptosis and inflammation via GRPR-dependent mechanism

•GRPR is a newly discovered target for acute kidney injury.•Aurantiamide is a novel GRPR antagonist with high efficiency and safety in the treatment of AKI.•Aurantiamide protected kidney function and attenuated renal inflammation and necroptosis in two cell models and three mouse models.•We performed aurantiamide’s target and efficacy in GRPR knockout mice.•We extracted primary cells to re-validate the target of aurantiamide’s action by cisplatin-induced mouse modeling.•Targeting GRPR using aurantiamide may serve as a potential clinical treatment strategy for AKI. Acute kidney injury (AKI) manifests as a clinical syndrome characterised by the rapid accumulation of metabolic wastes, such as blood creatinine and urea nitrogen, leading to a sudden decline in renal function. Currently, there is a lack of specific therapeutic drugs for AKI. Previously, we identified gastrin-releasing peptide receptor (GRPR) as a pathogenic factor in AKI. In this study, we investigated the therapeutic potential of a novel Chinese medicine monomer, aurantiamide (AA), which exhibits structural similarities to our previously reported GRPR antagonist, RH-1402. We compared the therapeutic efficacy of AA with RH-1402 both in vitro and in vivo using various AKI models. Our results demonstrated that, in vitro, AA attenuated injury, necroptosis, and inflammatory responses in human renal tubular epithelial cells subjected to repeated hypoxia/reoxygenation and lipopolysaccharide stimulation. In vivo, AA ameliorated renal tubular injury and inflammation in mouse models of ischemia/reperfusion and cecum ligation puncture-induced AKI, surpassing the efficacy of RH-1402. Furthermore, molecular docking and cellular thermal shift assay confirmed GRPR as a direct target of AA, which was further validated in primary cells. Notably, in GRPR-silenced HK-2 cells and GRPR systemic knockout mice, AA failed to mitigate renal inflammation and injury, underscoring the importance of GRPR in AA’s mechanism of action. In conclusion, our study has demonstrated that AA serve as a novel antagonist of GRPR and a promising clinical candidate for AKI treatment.