Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has emerged as a predominant cause of chronic liver disease globally, with its prevalence rising steadily each year. If left untreated, MASLD may progress to metabolic dysfunction in associated steatohepatitis (MASH), a more severe condition that can irreversibly advance to liver fibrosis, cirrhosis, and even hepatocyte carcinoma (HCC). Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD. This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD, as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies. Cyclocarya paliurus (Batal.) Iljinskaja, a plant known for both medicinal and dietary applications, has demonstrated diverse pharmacological properties, including hypoglycemic, lipid-regulating, and hepatoprotective effects. This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract (CCE) in a murine model of MASLD induced by a methionine-choline-deficient (MCD) diet. Simvastatin was employed as a positive control drug, while various doses of CCE were administered to assess its therapeutic potential. Meanwhile, the control and model groups received 0.5% sodium carboxymethyl cellulose (CMC-Na) once daily for 6 weeks. At the end of the treatment period, blood and liver samples were collected for biochemical analysis, histopathological assessment, and gene expression profiling. The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) while enhancing the activities of cholinesterase (CHE) and high-density lipoprotein cholesterol (HDL-C). In liver tissues, CCE markedly decreased the levels of total cholesterol (TC) and triglycerides (TG), while simultaneously increasing hepatic HDL-C content. Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice. Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis, including SREBP2, LDLR, and HMGCR. Concurrently, it upregulated the expression of genes and proteins related to cholesterol transport, such as ABCG5 and ABCG8. Additionally, CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines, including TNF-α and IL-6, and modulated oxidative stress markers, such as NRF2, KEAP1, and NQO1. Protein expression analyses revealed reduced levels of IL-6 and IL-1β, further corroborating its anti-inflammatory effects. In summary, C. paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice. These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2 (SREBP2). This study highlighted the therapeutic potential of C. paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.
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