黑色素瘤是高恶性、早转移、高死亡率的肿瘤，并呈现ROS代谢重编程的状态，其精细调控机制不明确。我们发现黑色素瘤中ROS高水平与Nrf2、NOX4异常表达密切相关，并且Nrf2有可能调控NOX4的表达。结合新近研究进展，提出假说：Keap1/Nrf2-NOX4系统平衡异常，同时Nrf2调控NOX4转录、促进ROS产生，Nrf2“双向”调控ROS代谢，以维持一定程度高的ROS水平，促进黑色素瘤发生发展。为证实此假说，首先观察黑色素瘤组织Keap1/Nrf2-NOX4系统表达异常、以及与患者结局的关系；然后用细胞模型和动物模型证实Keap1/Nrf2-NOX4系统在黑色素瘤ROS代谢重编程中的作用及其机制，观察干预这一系统对ROS代谢重编程的逆转作用；最后验证Nrf2调控NOX4的转录，促进ROS产生。该研究为阐明黑色素瘤ROS的精细调控机制，以及针对ROS干预治疗黑色素瘤提供前期工作基础。

Malignant melanoma is a highly deleterious illness characterized by early metastasis and high mortality. Metabolic reprogramming state, with a high intracellular ROS level than normal cells, which promotes the tumorigenesis and development, is typical in melanoma. However, regulatory mechanism of this metabolic change remains unclarified. Our previous studies have shown that high ROS level in the melanoma cell and tissue was closely related to the abnormal expressions of Nrf2 and NOX4, and NOX 4 expression might be regulated by the Nrf2. Combined with recent research progresses, it is hypothesized that the Keap1/Nrf2-NOX4 system displays an imbalance and Nrf2 regulates the transcription of NOX4, leading to increasing of ROS. The bi-directional regulation of ROS maintains a certain degree of high ROS level in order to promote the development of melanoma. To test this hypothesis, firstly, the status and balance of Keap1/Nrf2-NOX4 system in the malignant melanoma tissues will be assessed as well as their relationship with patient outcomes in clinical samples. Secondly, animal models and cellular experimental system will be applied to demonstrate the role of Keap1/Nrf2-NOX4 system and explore its mechanism in melanoma metabolism reprogramming. Moreover, effect on melanoma cell metabolism reprogramming by interference of Keap1/Nrf2-NOX4 system will be tested. Finally, verify the ROS production promoted by Nrf2 regulated transcription of NOX4. The results of this study will provide the foundation to clarify the regulatory mechanism of high ROS level in melanoma cells and a development of future intervention based on ROS regulation for melanoma treatment.