EGCG-Functionalized Selenium Nanoparticles Mitigate High-Fat Diet-Induced Hepatic Lipotoxicity Through Keap1/Nrf2 Redox Modulation and Transcriptional Regulation of AMPK/SIRT1/PGC-1α/MFN2-Associated Mitochondrial Homeostasis

High-fat diet (HFD)-induced hyperlipidemia is an experimental metabolic condition characterized primarily by dysregulated serum lipid levels and hepatic lipid accumulation, with associated oxidative, inflammatory, mitochondrial, and cardiovascular alterations. This study investigated the therapeutic efficacy of epigallocatechin gallate (EGCG)-functionalized selenium nanoparticles (EGCG-SeNPs) against HFD-induced metabolic and hepatic injury, in comparison with free EGCG, sodium selenite (Na2SeO3), and Lipanthyl. EGCG-SeNPs were characterized by dynamic light scattering, zeta potential analysis, transmission electron microscopy, X-ray diffraction, and UV–visible spectrophotometry. Forty-two adult male rats were allocated into six groups: control, HFD, HFD/Lipanthyl, HFD/EGCG, HFD/Na2SeO3, and HFD/EGCG-SeNPs. High-fat diet (HFD) feeding induced pronounced dyslipidemia, elevated hepatic enzymes, increased cardiac injury biomarkers, enhanced lipid peroxidation and nitrosative stress, depletion of antioxidant defenses, and disruption of the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) regulatory axis. HFD also increased nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), while altering mitochondrial apoptotic markers, including B-cell lymphoma 2 (Bcl-2), cytochrome c, and caspase-3. At the transcriptional level, HFD increased lipogenic gene expression and reduced the expression of genes related to fatty-acid oxidation, metabolic regulation, and mitochondrial homeostasis. EGCG-SeNPs showed the greatest overall improvement among the tested interventions, as indicated by an improved lipid profile, hepato-cardiac injury biomarkers, antioxidant status, inflammatory markers, apoptotic markers, hepatic architecture, and Nrf2 immunoreactivity. Collectively, EGCG-SeNPs may mitigate HFD-induced hepatic lipotoxicity and associated cardiac stress through coordinated modulation of lipid metabolism, redox balance, inflammation, and mitochondrial homeostasis.