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: 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.