Pakistan Journal of Pharmaceutical Sciences

Abstract: Objective The purpose of this investigation was to identify and confirm the molecular mechanisms through which naringenin exerts its therapeutic effects in sepsis-induced acute kidney injury (AKI), employing network pharmacology methodologies. Methods An integrative bioinformatics pipeline was deployed across multiple databases and analytical platforms to identify molecular targets, map protein interactome networks and assess functional annotation clusters. Molecular docking studies were executed to verify the findings. The efficacy was validated using a cecal ligation and puncture-induced AKI mouse model. Histopathological changes were assessed through hematoxylin-eosin staining. Biochemical parameters, including blood urea nitrogen (BUN) and creatinine (Cr), were quantified. Pro-inflammatory mediators (IL-1 and TNF-?) were evaluated via ELISA, while Nrf2 and HO-1 protein expression was determined through Western blot analysis. Results The network pharmacology analysis revealed 3,449 potential therapeutic targets of naringenin in AKI treatment. Target analysis demonstrated significant associations with oxidative stress response and apoptotic signaling cascades. KEGG pathway analysis highlighted the involvement of the Nrf2/HO-1 signaling axis in renal injury. Experimental results showed that naringenin improved pathological changes in AKI mice, down regulated serum BUN and Cr levels, reduced inflammatory factors IL-1 and TNF-? levels and decreased the expression of Nrf2 and HO-1 proteins in sepsis-related AKI. Conclusion The therapeutic efficacy of naringin in AKI is mediated through pleiotropic effects on multiple targets and signaling cascades, with its renoprotective mechanism primarily involving the regulation of Nrf2/HO-1 pathway-dependent oxidative stress reduction.