PARPi是目前卵巢癌治疗几十年来最重要的突破，已被纳入卵巢癌的初始维持治疗。然而，导致 PARPi 耐药的机制仍不清楚。我们的研究旨在筛选新靶点以更好地预测和逆转 PARPi 耐药性并探索潜在机制。在这里，我们对 TCGA 卵巢癌队列中铂敏感组和铂耐药组之间的差异表达基因进行了比较分析。分析表明，与TCGA-OV队列中的铂类耐药个体相比，lncRNA PART1在铂类敏感患者中显着高表达，并在GEO数据集和齐鲁医院队列中得到进一步验证。此外，PART1的上调与卵巢癌的良好预后呈正相关。此外，体外和体内实验表明，抑制 PART1 会赋予对顺铂和 PARP 抑制剂的耐药性，并促进细胞衰老。衰老细胞对化疗药物的抵抗力更强。 RNA 反义纯化和 RNA 免疫沉淀测定揭示了 PART1 和 PHB2（一种重要的线粒体自噬受体）之间的相互作用。 PART1 的敲低可以促进 PHB2 的降解，损害线粒体自噬并导致细胞衰老。拯救实验表明，PHB2 的过度表达显着降低了对 PARPi 的抵抗力以及 PART1 敲低引起的细胞衰老。利用 PDX 模型进一步证实了研究结果。总而言之，我们的研究表明，lncRNA PART1 有潜力成为逆转 PARPi 耐药性并改善卵巢癌预后的新靶标。版权所有 © 2024。由 Elsevier B.V. 出版。

PARPi is currently the most important breakthrough in the treatment of ovarian cancer in decades, and it has been integrated into the initial maintenance therapy for ovarian cancer. However, the mechanism leading to PARPi resistance remains unelucidated. Our study aims to screen novel targets to better predict and reverse resistance to PARPi and explore the potential mechanism. Here, we conducted a comparative analysis of differentially expressed genes between platinum-sensitive and platinum-resistant groups within the TCGA ovarian cancer cohort. The analysis indicated that lncRNA PART1 was significantly highly expressed in platinum-sensitive patients compared to platinum-resistant individuals in TCGA-OV cohort and further validated in the GEO dataset and Qilu hospital cohort. Moreover, the upregulation of PART1 was positively correlated with a favorable prognosis in ovarian cancer. Furthermore, in vitro and in vivo experiments showed that inhibition of PART1 confers resistance to both cisplatin and PARP inhibitor and promotes cellular senescence. Senescent cells are more resistant to chemotherapeutics. RNA antisense purification and RNA immunoprecipitation assays revealed an interaction between PART1 and PHB2, a crucial mitophagy receptor. Knockdown of PART1 could promote the degradation of PHB2, impairing mitophagy and leading to cellular senescence. Rescue assays indicated that overexpression of PHB2 remarkably diminished the resistance to PARPi and cellular senescence caused by PART1 knockdown. PDX models were utilized to further confirm the findings. Altogether, our study demonstrated that lncRNA PART1 has the potential to serves as a novel promising target to reverse resistance to PARPi and improve prognosis in ovarian cancer.Copyright © 2024. Published by Elsevier B.V.