甲状腺癌已成为最常见的内分泌相关恶性肿瘤。目前，越来越多的证据支持扩展PARP抑制剂在BRCA突变癌症之外的临床策略的效益。然而，PARP抑制剂在甲状腺癌中的功能和分子机制尚未完全理解。在这里，一方面，我们发现niraparib促进了甲状腺癌中DNA损伤的积累。另一方面，我们指出niraparib通过促进依赖于PAR的方式抑制DIMT1的转录，随后导致甲状腺癌中全局翻译抑制。同时，我们发现niraparib通过抑制p65的PARylation激活了NF-κB信号通路，从而通过E3泛素连接酶RNF146降低其泛素化和降解水平。此外，博泰泽米布（一种小分子抑制剂）能够显著增强niraparib在甲状腺癌中的抗肿瘤效应，无论是体外还是体内。我们的发现为BRCA突变癌细胞中PARP抑制剂的疗效提供了机制支持。©作者。

Thyroid cancer has become the most frequent endocrine-related malignancy. Currently, a mounting body of evidences support the clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers. However, the functions and molecular mechanisms of PARP inhibitors in thyroid cancers (TCs) are not fully understood. Here, on the one hand, we revealed that niraparib promotes the accumulation of DNA damage in TCs. On the other hand, we indicated that niraparib inhibits the transcription of DIMT1 through promoting Pol II pausing in a PAR-dependent manner, subsequently leading to a global translation inhibition in TCs. Meanwhile, we found that niraparib activates the NF-κB signaling pathway by inhibiting the PARylation of p65, which decreases its ubiquitination and degradation level through E3 ubiquitin ligase RNF146. Moreover, bortezomib (a small molecule inhibitor of the NF-κB signaling pathway) could significantly enhance the anti-tumor effect of niraparib on TCs in vitro and in vivo. Our findings provide mechanistic supports for the efficacy of PARP inhibitors in cancer cells lacking BRCA-mutant.© The author(s).