Visnagin Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting Oxidative Stress and Reducing Ferroptosis

Background and Objective: Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening condition driven by oxidative stress, ferroptosis, and inflammation, yet effective treatments remain unavailable. Visnagin has antioxidant and anti-inflammatory properties and has been traditionally used for cardiovascular and renal disorders, but its role in modulating ferroptosis and redox imbalance in SA-AKI remains unclear. Thus, the study investigated the renoprotective effects of visnagin in a murine lipopolysaccharide (LPS)-induced AKI model, focusing on oxidative stress and ferroptosis. Methods: A systems pharmacology approach integrating network-based target prediction and molecular docking identified candidate targets. In vivo and in vitro validations in LPS-induced AKI mice and HK-2 cells assessed histopathology, oxidative biomarkers, ferroptosis mediators, and key signaling pathways. Results: Visnagin demonstrated affinity binding to AKT1, NFE2L2, ACSL4, and TFRC, indicating a potential role in modulating oxidative stress and ferroptosis. In vivo, visnagin alleviated renal injury, reduced lipid peroxidation, and downregulated ACSL4 and TfR1 expression, with this accompanied by reduction in renal Fe2+ levels. Although visnagin reduced the protein abundance of SOD, catalase, and GSH-Px, it markedly enhanced their enzymatic activities, likely due to decreased oxidative burden and preservation of enzyme functionality under LPS-induced stress. Additionally, visnagin inhibited p-Akt and p-Nrf2, suggesting suppression of upstream signaling pathways. In vitro, visnagin reduced intracellular ROS levels in HK-2 cells and exhibited scavenging activity against various radical species. Conclusions: Visnagin exerts protective actions through both modulation of Akt/Nrf2 signaling ACSL4/TfR1 signaling and direct free radical scavenging. These findings underscore visnagin’s potential as a multitarget therapeutic agent for SA-AKI.