膀胱癌是常见的恶性肿瘤之一，占我国泌尿生殖系肿瘤发病率的第一位。化疗耐药是膀胱癌临床治疗中的一个棘手问题。RIP3是诱导程序性坏死的标志蛋白，在肿瘤凋亡通路障碍的情况下，扮演重要角色。前期发现：紫草萘醌类成分中含有以RIP3为靶点且对膀胱癌有显著效果的活性化合物。基因沉默RIP3显著抑制了目标化合物诱导的RIP3、p62和LC3Ⅱ蛋白表达以及p62/RIP3复合体的形成。此外，RIP3的下调，导致p62/Keap1复合体的进一步形成以及Nrf2蛋白的显著升高。由此推测，在膀胱癌中RIP3可能通过p62磷酸化调控Keap1/Nrf2耐药途径，诱导自噬促进死亡和抗转移，但具体药效物质及复合体相互作用机制尚不清晰。本项目拟从分子靶点RIP3入手，探寻紫草萘醌类活性化合物，阐明RIP3/p62/Keap1复合体调控体系对膀胱癌存活、自噬及转移过程中的作用机制，为膀胱癌临床靶向药物研发提共依据。

Bladder cancer is one of the common malignant tumors in the urinary system, accounting for the first incidence of urogenital tumors in China and showing an increasing trend year by year. Chemotherapy resistance is a thorny issue in the clinical treatment of bladder cancer. RIP3 is a marker protein that induces programmed necrosis and plays an important role in the case of tumor apoptotic pathway disorders. Our previous study discovered that naphthoquinone contains active compounds that targets RIP3 and has significant effect on bladder cancer. Gene silencing RIP3 significantly inhibited the expression of RIP3, p62 and LC3II proteins and the formation of the p62/RIP3 complex induced by naphthoquinone active compounds. Furthermore, down-regulation of RIP3 resulted in further formation of the p62/Keap1 complex and a significant increase in Nrf2 protein. Therefore, we hypothesis that RIP3 may regulate the Keap1/Nrf2 resistance pathway through p62 phosphorylation in bladder cancer, and induce autophagy to promote bladder cancer cell death and anti-metastasis. However, the specific mechanism of the interaction between naphthoquinone active substances and complexes is not clear. This project intends to start from the molecular target RIP3 to explore the active compounds of Chinese medicine naphthoquinone active compounds and clarify the mechanism of RIP3/p62/Keap1 complex regulation system in bladder cancer survival, autophagy and metastasis. To provide the basis for the development of clinical targeted drugs.