Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major global health concern linked to oxidative stress, dyslipidemia, and hepatocellular carcinoma. Environmentally friendly copper nanoparticles (CuONPs) synthesized using onion peel extract, rich in polyphenols, may offer antioxidant, hepatoprotective, and anticancer benefits. This study aimed to evaluate the anti-oxidative stress and cytotoxic potential of these CuONPs in NAFLD using combined in vivo and in vitro models. Onion peel extract (OPE) was prepared with ethanol, and CuNPs were synthesized using standard protocols. Fifty male rats were divided into five groups (control, high-fat diet, OPE, CuONPs, OPE-CuONPs) for 8 weeks. Liver function (ALT, AST, ALP), antioxidant parameters (SOD, CAT, MDA), and lipid profiles were assessed. In vitro, HepG2 and SNU-423 cancer cells, along with normal hepatic cells (HdFn), were exposed to CuONPs. Cell viability, mitochondrial function, nuclear morphology, apoptotic pathways (caspase-8/9), and antioxidant gene expression (GPx1) were evaluated. High-fat diet induced oxidative stress, dyslipidemia, and elevated liver enzymes in rats. Treatment with OPE, CuONPs, and especially OPE-CuONPs improved liver markers, antioxidant defenses, and lipid profiles. In vitro, CuONPs selectively induced cytotoxicity, mitochondrial dysfunction, and apoptosis in cancer cells, while sparing normal cells. GPx1 expression changes supported the observed antioxidant effects. Onion peel-mediated CuONPs exhibit potent hepatoprotective, antioxidant, and anticancer properties, improving lipid metabolism, enhancing antioxidant defenses, and inducing apoptosis in hepatocellular carcinoma cells with minimal toxicity to normal liver cells. These findings support their potential use in treating NAFLD and liver cancer.