Sepsis-associated acute kidney injury (AKI) is a life-threatening complication marked by inflammation-driven renal dysfunction. Although advances have been made in supportive care, pharmacologic therapies targeting the underlying molecular mechanisms of sepsis-associated AKI are lacking. Visnagin, a furanochromone derivative with anti-inflammatory properties, has yet to be explored in treatment for sepsis-associated AKI.

This study used a network pharmacology approach to identify visnagin targets associated with AKI. We conducted gene enrichment and protein-protein interaction analyses and performed molecular docking to predict binding affinities between visnagin and key inflammatory proteins. An in vivo murine model of LPS-induced AKI was established to evaluate the protection of visnagin. Renal function was assessed through serum creatinine and blood urea nitrogen levels. Additionally, histological injury, inflammatory cytokine expression, and molecular pathways were analysed.

Bioinformatics analyses identified MAPK1, MAPK14, NFKB1, and CASP1 as hub genes potentially targeted by visnagin. Molecular docking confirmed strong binding affinities between visnagin and these proteins that exceeded the binding affinity of dexamethasone in key inflammatory targets. In vivo, visnagin substantially reduced LPS-induced renal dysfunction and histopathological damage in a dose-dependent manner. Visnagin suppressed the phosphorylation of p38 MAPK and extracellular signal-related kinase, decreased NF-κB activation, and inhibited the generation of proinflammatory cytokines. Moreover, visnagin attenuated pyroptosis by inhibiting the NLRP3/apoptosis-associated-speck-like-protein-containing-a-caspase-recruitment-domain/caspase-1/Gasdermin-D axis.

Visnagin mitigates LPS-induced AKI by targeting multiple signalling pathways, particularly NF-κB-mediated inflammation and NLRP3 inflammasome-mediated pyroptosis. These findings suggest that visnagin is a promising multitarget candidate for treating sepsis-associated AKI.