2026/05/08 by Nasreen S. Hamad, Dlzar D. Ghafoor, Hezha O. Rasul
paper · doi:10.1002/jat.70240
ABSTRACT Resveratrol is widely studied for its anti‐inflammatory properties, yet the dose–response relationship between its molecular effects and potential organ toxicity in healthy animals remains poorly characterized. This study investigated whether the doses that suppress NF‐κB signaling overlap with those causing measurable hepato–renal injury in healthy female rats. Rats received saline control, vehicle control (10% DMSO in saline), or resveratrol at 5, 10, 20, or 30 mg/kg by oral gavage every 72 h for 21 days, corresponding to seven doses. Plasma hepatic and renal biochemistry and oxidative stress markers were measured using standardized assays. NF‐κB p65 DNA‐binding activity was quantified in liver nuclear extracts using ELISA. Liver, kidney, heart, and spleen tissues were processed for H&E histology with blinded semiquantitative scoring and ImageJ‐based morphometry. Correlations between dose and biochemical parameters were assessed using Spearman's rank correlation on individual–animal data. Resveratrol produced a dose‐dependent pattern of organ injury. Mild histological changes were observed at 5–10 mg/kg, whereas more pronounced degenerative and inflammatory alterations were observed at 20–30 mg/kg in the liver and kidney. Plasma AST showed a significant dose‐related increase after FDR correction ( q = 0.0445), while ALT, ALP, and urea showed nominal increases that did not remain significant after correction. Hepatic NF‐κB p65 DNA‐binding activity was significantly suppressed in a dose‐dependent manner ( q = 0.049), with the greatest suppression at 20–30 mg/kg, the same dose range in which histological injury was most evident. Exploratory individual‐level analysis suggested that greater NF‐κB suppression tended to co‐occur with higher hepatic lesion scores. Plasma oxidative‐stress markers showed no consistent dose‐related differences. These findings indicate that, in healthy rats, the dose range associated with effective NF‐κB modulation (≥ 20 mg/kg) overlaps with the threshold for measurable hepato–renal injury. This overlap defines a narrow therapeutic window and highlights the importance of dose justification and safety monitoring in resveratrol supplementation and clinical studies.