<p>To understand the role of palmitic acid overload on renal physiology, we exposed female rats to palmitic acid (PA) beyond the physiological range reminiscent of a high-fat western diet. We then treated the rats with graded doses of lycopene (Lyc) to evaluate its potential remedial effect against PA-induced renal injury. Twenty-four rats were randomized into four groups as control (received vehicles; Free Fatty Acid Free Bovine Serum Albumin (BSA) and Olive oil; PA only [received 5 mM BSA-complexed PA]; while the other two groups received 10 and 20 mg/kg body weight of Lyc along with the BSA-complexed PA. The Olive oil-reconstituted Lyc was commenced at the seventh week of intraperitoneal PA injection (uninterrupted) until the nineth week. Our results show that palmitic acid PA overload caused renal lipid dystrophy, characterized by decreased cholesterol, triglycerides, and phospholipids. We also observed elevated activities of lactate dehydrogenase and decreased activity of alanine aminotransferase. The activities of superoxide dismutase, myeloperoxidase, and malondialdehyde levels increased, while glutathione peroxidase activity decreased significantly. Furthermore, PA-induced disruption of cellular electrolytes is characterized by decreased calcium, chloride, sodium, and magnesium ions, and elevated activities of Na⁺/K⁺, and Ca²⁺/Mg²⁺ ATPases. Western blot analysis shows decreased Nrf2 expression, while NF-^KB and Toll -Like Receptor 4 (TLR4) increased. Furthermore, the mRNA expression of TLR4, IL-6, TNF-alpha, and IL-1β increased, while IL-10 decreased in PA only group. However, Lyc treated groups exhibits meaningful ameliorative potentials by abating oxidative stress, inflammation, lipid dystrophy, and iono-dysregulation. This study suggests lycopene supplementation might abate PA -invoked disruption of lipid metabolism, inflammatory signal propagation and disruption of innate antioxidant systems in female albino rats.</p>