Tangeretin regulates oxidative stress in cutaneous melanoma cells via the Nrf2 signaling pathway

Oxidative stress is a key factor in melanoma progression, making it an important therapeutic target. This study explored the effects of tangeretin, a citrus-derived flavonoid, on human melanoma A375 cells and its underlying mechanisms. A375 cells were treated with tangeretin at various concentrations. The effects of tangeretin on cell proliferation, migration, invasion, and apoptosis were assessed using MTT, wound healing, Transwell invasion, and flow cytometry assays, respectively. Oxidative stress markers, including reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), were evaluated. Western blot was used to measure the expression levels of key proteins in the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and apoptosis-related markers. The results showed that tangeretin significantly inhibited cell proliferation in a dose-dependent manner, induced apoptosis by increasing the Bax/Bcl-2 ratio, and suppressed cell migration and invasion. Additionally, tangeretin reduced oxidative stress by decreasing ROS and MDA levels while enhancing GSH content and SOD activity. Mechanistically, tangeretin activated the Nrf2 signaling pathway, increasing the expression of Nrf2 and its downstream antioxidant proteins heme oxygenase-1, quinone oxidoreductase 1, and γ-Glutamylcysteine synthetase. These findings suggest that tangeretin exerts anti-cancer effects on melanoma cells by regulating oxidative stress, inhibiting proliferation and metastasis, and inducing apoptosis via the Nrf2 pathway. Tangeretin may serve as a promising candidate for melanoma treatment.