Quercetin-mediated selenium nanoparticles protect against hyperthyroidism-induced hepatic injury: Involvement of Nrf2/NF-κB signaling, mitochondrial apoptosis, and iron/heme imbalance.

PURPOSE: Hyperthyroidism-associated liver injury represents an important extra-thyroidal complication of thyroid hormone excess, driven by increased metabolic demand and interconnected oxidative, inflammatory, and mitochondrial disturbances. However, the coordinated involvement of Nrf2/NF-κB signaling, apoptosis, and iron/heme dysregulation remains insufficiently understood, highlighting the need for hepatoprotective strategies. Therefore, this study evaluated the hepatoprotective efficacy of quercetin-mediated selenium nanoparticles (QUR-SeNPs) against L-thyroxine-induced hyperthyroidism in rats and compared their effects with free quercetin and sodium selenite.

METHODS

QUR-SeNPs were synthesized and characterized using dynamic light scattering, zeta potential analysis, and transmission electron microscopy. Forty male albino rats were divided into five groups: Normal, hyperthyroid (HPT), HPT&Na₂SeO₃, HPT&QUR, and HPT&QUR-SeNPs. Thyroid hormone profile, liver function biomarkers, oxidative/antioxidant status, inflammatory mediators, apoptotic markers, iron homeostasis, hepatic iron/heme-related gene expression, Nrf2 immunoexpression, and histopathological alterations were assessed.

RESULTS

L-thyroxine induced a hyperthyroid state associated with hepatic dysfunction, oxidative/nitrosative stress, impaired Nrf2/Nfe2l2 antioxidant signaling, NF-κB-mediated inflammation, mitochondrial apoptotic activation, and disrupted systemic and hepatic iron homeostasis. QUR-SeNPs markedly improved the circulating thyroid hormone profile, improved liver enzyme activities, reduced NO, MDA, and Keap-1, enhanced GSH and antioxidant enzymes, suppressed TNF-α, IL-6, COX-2, and NF-κB, and normalized Bax/Bcl-2/caspase-3 signaling. Moreover, QUR-SeNPs corrected iron imbalance, regulated Hamp1, Tfr1, Ftl, ALAS1, and HRI expression, restored Nrf2 immunoexpression, and improved hepatic histoarchitecture.

CONCLUSION

QUR-SeNPs exerted greater modulating the Nrf2/NF-κB pathways role in hepatoprotection compared with free quercetin and sodium selenite, suggesting their therapeutic promise against hyperthyroidism-induced liver injury through coordinated regulation of redox, inflammatory, apoptotic, and iron/heme metabolic pathways.