Background <p>A major global public health concern is the widespread and illegal use of mercury compounds in skin-lightening cosmetics, mainly because of their extreme systemic toxicity, especially to the kidneys. Imperatorin is a promising natural furanocoumarin compound with high antioxidant properties. This study investigates the mechanism of mercury-induced nephrotoxicity and the curative properties of imperatorin, focusing on the NF-κB, MAPKs, and Nrf2 signalling pathways.</p> Methods <p>Rats were divided into control, mercury-chloride (HgCl₂)-treated (2.5&#xa0;mg/kg), imperatorin-treated (15&#xa0;mg/kg), and two co-treated groups receiving HgCl₂ (2.5&#xa0;mg/kg) with either 10&#xa0;mg/kg or 15&#xa0;mg/kg of imperatorin. Our study examined tissue histopathology, renal function markers, oxidative stress parameters, inflammatory cytokines, as well as the expression of nephrin, podocin, Kidney Injury Marker-1 (KIM-1), Nrf2, NF-kB, p38, ERK, and JNK mRNA levels. Further, the activated protein levels of p38, ERK and JNK were confirmed using a western blot.</p> Results <p>Imperatorin decreased the levels of creatinine, urea, and uric acid; increased protein and albumin levels and restored pathological changes in a dose-dependent manner. The antioxidant levels of superoxide dismutase, reduced glutathione, glutathione peroxidase and catalase were also restored by imperatorin treatment while modulating the levels of ROS, MDA, TNF-α, IL-6 and IL-1β. Gene expression analysis showed a significant increase in KIM-1 and a decrease in nephrin and podocin levels in the HgCl₂ group, suggesting kidney injury. Imperatorin modulated the gene expression levels of MAPKs (p38, Erk, and Jnk), Nrf2, and NF-κB in the HgCl₂ groups. Protein expression levels of MAPKs confirmed that MAPK signal activation in the HgCl₂ group decreased by imperatorin treatment.</p> Conclusion <p>These results show that in an in vivo model, imperatorin provides significant protection against HgCl₂-induced nephrotoxicity.</p>