Potential Mechanism of Perillaldehyde in the Treatment of Nonalcoholic Fatty Liver Disease Based on Network Pharmacology and Molecular Docking

Background: Non-alcoholic fatty liver disease (NAFLD) is a common chronic metabolic liver disease worldwide, and it has become a major public health issue. Perillaldehyde (PA), a type of terpenoid compound, has unique pharmacological activities. Purpose: This study aims to explore the pharmacological effects of PA on NAFLD and its potential mechanisms using network pharmacology, molecular docking, and in vitro animal experiments. Experimental approach: Firstly, network pharmacology and molecular docking identified the core targets and related signaling pathways for PA treatment of NAFLD. Subsequently, H&E and Masson staining, immunofluorescence, immunohistochemistry, and Western blotting experiments were conducted to validate the results predicted by network pharmacology. Key Results: Network pharmacology analysis indicated that PPAR-α might be the core target of PA intervention in NAFLD. H&E and Masson staining showed that after low-dose (50mg/kg) PA treatment, the fat deposition in the livers of NAFLD mice significantly improved, and liver tissue fibrosis was reduced. Immunohistochemistry and immunofluorescence analysis demonstrated that after low-dose (50mg/kg) PA treatment, the content of pro-apoptotic protein Bax dramatically decreased. In contrast, the expression of anti-apoptotic protein Bcl-2 prominently increased, thereby inhibiting liver cell apoptosis in NAFLD mice. Western blot results directly confirmed that low-dose (50mg/kg) PA could increase the expression of PPAR-α in the body and inhibit the expression of NF-κB. Conclusions &Implications: Based on these findings, we concluded that PA targets the activation of PPAR-α, inhibits NF-κB, promotes lipid metabolism in liver cells of NAFLD mice, and inhibits liver cell apoptosis in NAFLD mice.