Potential mechanism of perillaldehyde in the treatment of nonalcoholic fatty liver disease based on network pharmacology and molecular docking

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic metabolic liver diseases worldwide. Perillaldehyde (4-propyl-1-en-2-ylcyclohexene-1-aldehyde, PA) is a terpenoid compound extracted from Perilla, which has effective pharmacological activities such as anti-inflammatory, antidepressant, and anticancer. This study aimed to explore the pharmacological effects of PA in intervening with NAFLD and reveal its potential mechanisms. Firstly, we identified the core targets of PA intervention therapy for NAFLD through network pharmacology and molecular docking techniques. After that, in vitro animal experiments such as H&E and Masson staining, immunofluorescence, immunohistochemistry, and Western blot were conducted to validate the results network effectively pharmacology predicted. Network pharmacology analysis suggested that PPAR-α may be the core target of PA intervention in NAFLD. H&E and Masson staining showed that after low-dose (50 mg/kg) PA administration, there was a noticeable improvement in fat deposition in the livers of NAFLD mice, and liver tissue fibrosis was alleviated. Immunohistochemical and immunofluorescence analysis showed that low dose (50 mg/kg) PA could reduce hepatocyte apoptosis, decrease the content of pro-apoptosis protein Bax, and increase the expression of anti-apoptosis protein Bcl-2 in NAFLD mice. Western blot results confirmed that low-dose (50 mg/kg) PA could increase the expression of PPAR-α and inhibit the expression of NF-κB in NAFLD mice. Our study indicated that PA could enhance the activity of PPAR-α and reduce the level of NF-κB in NAFLD mice, which may positively affect the prevention of NAFLD.