Chemopreventive Effects of <em>Citrus depressa</em> Leaf Extract Through Nrf2 Pathway Activation and Epigenetic Modulation

Many chronic diseases, including cancer, can be developed in conjunction with excessive intracellular oxidative stress and persistent inflammation. The importance of preventive strategies is highlighted by the potential of phytochemical interventions to mitigate these diseases. The purpose of this study was to investigate how Citrus depressa leaf (CDL) extracts can prevent TPA-induced carcinogenesis in mouse JB6 P+ skin epidermal cells. Both the water extract (CDL-WE) and the 95% ethanol extract (CDL-95EE) contain abundant flavonoids that inhibit TPA-induced cell transformation and colony formation without minimal cytotoxicity. Mechanistic studies indicated that CDL-95EE increased the gene expression of Nrf2-related detoxification and antioxidant enzymes such as UGT1A and HO-1, and decreased the accumulation of intracellular ROS. Furthermore, CDL-95EE also reduced the expression of epigenetic modifiers, including DNA and histone deacetylases (HDACs), suggesting that it is involved in epigenetic regulation. These findings indicate that CDL, an agricultural by-product, may be useful in cancer prevention through antioxidant and epigenetic mechanisms.