过氧化物酶体HSD17B4调控脂肪酸代谢促进卵巢癌耐药的作用与机制研究

卵巢癌是病死率最高的妇科恶性肿瘤，分子靶向治疗的匮乏和化疗耐药的普遍发生制约了生存率的提高。前期研究中，我们通过比较化疗敏感和化疗耐药的卵巢癌临床样本，发现耐药肿瘤细胞过氧化物酶体显著上调；深入分析后，我们发现过氧化物酶体中负责脂肪酸氧化的HSD17B4蛋白在卵巢癌组织中呈现富集，并与卵巢癌患者预后相关；我们筛选到特异性抑制HSD17B4的小分子化合物，其具有良好的抗卵巢癌细胞增殖和化疗增敏效果。在这些预实验结果的基础上，我们申请本项目旨在进一步确定卵巢癌过氧化物酶体中HSD17B4的生物学功能，明确HSD17B4通过调控脂肪酸代谢促进卵巢癌耐药的分子机理，探索利用HSD17B4抑制剂靶向治疗卵巢癌并增强化疗效应的可行性。这些研究将增加我们对卵巢癌致病及耐药机制的理解，发现靶向卵巢癌并克服耐药性的有效策略，促进过氧化物酶体相关药物的临床研发。

Ovarian cancer (OC) is the leading cause of death among gynecologic malignancies, with limited survival improvement over the past decades due to chemotherapy drug resistance and insufficient effective molecular target therapies. Comparing clinical samples of platinum-resistant OC and platinum-sensitive OC, we found an up-regulated expression of peroxisome in platinum-resistant OC tissues. Furthermore, the enrichment of HSD17B4 protein, which was reported to be a critical factor in fatty acid oxidation in peroxisome, was observed in ovarian cancer tissues and related to the survival of patients. Then, we constructed and screened the specific inhibitor of HSD17B4, and proved its potential function in antitumor activity and improvement of chemo-sensitivity in both chemosensitive and chemoresistant ovarian cancer cells. . This study aims to verify the biological function of HSD17B4 in peroxisome, confirm the mechanism of HSD17B4 promoting drug resistance by regulating fatty acid metabolism, and explore the application of HSD17B4 inhibitor as a potential target drug in OC. Given this, we will make profound comprehension of pathogenesis and chemoresistance of OC, find out effective strategies for target therapy in OC, and promote drug development associated with peroxisome.