Abstract

Network pharmacology predicts that the PPARγ-p53 pathway is a key target mediating naringin’s effects. • Naringin regulates PPARγ/p53 pathway activity to counteract LPS-induced HK2 cell damage. • Naringin alleviates LPS-induced HK2 cell injury and inhibits ferroptosis in vitro. Background Sepsis-associated acute kidney injury (SA-AKI) is a common sepsis complication with complex pathogenesis and limited treatments, and ferroptosis has been reported to be involved in its development. While naringin protects against ischemia-reperfusion-induced renal injury, its function and mechanisms in SA-AKI remain elusive. Methods Ferroptosis-related targets, SA-AKI-related targets, and naringin-acting targets were obtained via the FerrDb, GeneCards, SwissTargetPrediction, and CTD databases, respectively. Overlapping targets were screened through Venn diagram analysis. A protein-protein interaction (PPI) network was constructed using the STRING platform, and GO and KEGG enrichment analyses were performed via DAVID. Subsequently, an SA-AKI cell model was established using LPS-stimulated HK2 cells. Protein expression, cell viability, and apoptosis were detected by Western blot, CCK-8 assay, and flow cytometry. Inflammatory factors (TNF-α, IL-6, and IL-1β) were examined by ELISA, while oxidative stress and ferroptosis biomarkers (ROS, lipid ROS, MDA, GSH, and Fe 2 + ) were measured using commercial kits. Results 14 overlapping targets among naringin, SA-AKI, and ferroptosis were identified. Enrichment analyses indicated that these targets were primarily involved in processes related to apoptosis, oxidative stress, signal transduction, and gene expression regulation. In silico molecular docking predicted that naringin bound to peroxisome proliferator-activated receptor gamma (PPARγ) and p53 with favorable binding energies (-9.0 and −7.9 kcal/mol). In vitro experiments demonstrated that naringin upregulated PPARγ protein expression and downregulated p53 expression in LPS-induce