Isorhoifolin attenuates cadmium-induced hepatotoxicity by modulating TLR4/MyD88/TRAF6/NF-κB and Nrf2/Keap1 pathways: a biochemical and histological study.

Abstract

BACKGROUND: Cadmium (Cd) is a ubiquitous environmental contaminant that can be readily deposited in the liver and negatively impact liver health. Isorhoifolin (IRF) is a naturally occurring flavonoid glycoside with a variety of pharmacological properties. This research was designed to assess the protective effects of IRF against Cd-induced hepatic injury. METHODS AND RESULTS: All the rats were divided into 4 groups: control, Cd (5 mg/kg), Cd + IRF (5 mg/kg + 10 mg/kg), and IRF (10 mg/kg), and the doses were administered for 30 days. Following the trial completion, all the animals were sacrificed, and further analyses were performed. Cd intoxication decreased the expression of Nrf2 and HO-1 while increasing Keap1. The results showed that the expressions and the activities of antioxidant enzymes, i.e., glutathione peroxidase (GPx), glutathione reductase (GSR), catalase (CAT), and superoxide dismutase (SOD), were lowered, while the levels of ROS and MDA were raised. Moreover, it activated the expression of MYD88, TLR4, IKKβ, and TRAF6, which further stimulated the expression of NF-κB, reducing IκB-α while elevating inflammatory marker levels, including IL-6, IL-1β, cyclooxygenase-2, and TNF-α. Besides, Cd intoxication increased the levels of liver function markers, i.e., AST, ALT, and ALP. Results showed that Cd exposure substantially downregulated BCL-2 mRNA expression, upregulated the apoptotic proteins BAX and CASPASE-3, and caused severe histopathological damage. However, IRF attenuated all the above-mentioned damages and preserved hepatic tissue architecture. CONCLUSIONS: These findings underscore the pharmacotherapeutic role of IRF in counteracting Cd-induced liver injury owing to its antiapoptotic, anti-inflammatory, and antioxidant nature.

Key Findings

• Cadmium intoxication decreased Nrf2 and HO-1 expression while increasing Keap1, leading to reduced antioxidant enzyme activities and increased oxidative stress markers (ROS and MDA).
• Cadmium exposure activated TLR4/MyD88/TRAF6/NF-κB inflammatory signaling pathways, increasing pro-inflammatory cytokines and liver damage markers.
• Isorhoifolin treatment attenuated cadmium-induced oxidative stress, inflammation, apoptosis, and preserved liver tissue architecture.

Clinical Significance

Citation

Ghafoor Naila, Munir Amna, Batool Moazamaet al.. Isorhoifolin attenuates cadmium-induced hepatotoxicity by modulating TLR4/MyD88/TRAF6/NF-κB and Nrf2/Keap1 pathways: a biochemical and histological study. Molecular biology reports. 2026-Oct-25.