核仁和纺锤体相关蛋白 1 (NUSAP1) 是一种微管相关蛋白，最近被发现表现出与各种癌症类型的恶性肿瘤发生和进展相关的异常表达模式。然而，NUSAP1 在肺腺癌 (LUAD) 中的具体调控机制和潜在的靶向治疗在很大程度上仍不清楚。在本研究中，通过进行生物信息学分析以及体外和体内实验，我们发现 NUSAP1 在 LUAD 中显着上调，与较差的总体生存率、较高的免疫原性和免疫浸润得分以及敏感性增加显着相关LUAD 中的常规化疗药物如紫杉醇、多西紫杉醇和长春瑞滨。从功能上来说，NUSAP1 过表达显着促进 LUAD 细胞增殖，而其敲低则显着抑制这一过程。有趣的是，我们的结果表明 NUSAP1 上调是由雌激素通过 ERβ 激活介导的。此外，我们确定恩替司他是一种新型的 NUSAP1 抑制剂。使用氟维司群（ERβ 拮抗剂）或恩替司他（新型 NUSAP1 抑制剂）以 ERβ/NUSAP1 轴为药理学靶标，可显着降低体外和体内 LUAD 的生长，这可能代表 LUAD 患者的有效替代治疗策略。© 作者。

Nucleolar and spindle-associated protein 1 (NUSAP1), a microtubule-associated protein, has been recently identified to exhibit aberrant expression patterns that correlate with malignant tumorigenesis and progression across various cancer types. However, the specific regulatory mechanisms and potential targeting therapies of NUSAP1 in lung adenocarcinoma (LUAD) remain largely elusive. In this study, by conducting bioinformatics analyses as well as in vitro and in vivo experiments, we identified that NUSAP1 was significantly upregulated in LUAD, with a notable correlation with poorer overall survival, higher scores for immunogenicity and immune infiltration, as well as increased sensitivity to conventional chemotherapeutic drugs such as paclitaxel, docetaxel and vinorelbine in LUAD. Functionally, NUSAP1 overexpression significantly promoted LUAD cell proliferation, while its knockdown markedly suppressed this process. Interestingly, our results revealed that NUSAP1 upregulation was mediated by estrogen via ERβ activation. Furthermore, we identified entinostat as a novel inhibitor of NUSAP1. Pharmacological targeting ERβ/NUSAP1 axis with fulvestrant (ERβ antagonist) or entinostat (novel NUSAP1 inhibitor) significantly reduced LUAD growth both in vitro and in vivo, which may represent effective alternative therapeutic strategies for patients with LUAD.© The author(s).