非小细胞肺癌（NSCLC）的药物治疗一直存在毒副作用、获得性耐药、适用人群狭窄等问题。在本研究中，我们建立了一种新颖的网络分析方法（差异-相关-富集-因果-节点），该方法基于差异分析、Spearman相关网络分析、生物功能分析和贝叶斯因果网络分析来发现新的治疗靶点BEAS-2B 和 7 个 NSCLC 细胞系的测序数据中的 NSCLC。我们的结果表明，PSMD2作为细胞周期网络中央的蛋白酶体亚基编码基因，与预后相关，是NSCLC患者的独立预后因素。 PSMD2的敲除通过诱导细胞周期停滞来抑制NSCLC细胞的增殖，并表现出细胞周期阻断蛋白p21、p27的显着增加以及细胞周期驱动蛋白CDK4、CDK6、CCND1和CCNE1的减少。 IPA 和分子对接表明，与报道的靶标 PSMB1 和 PSMB5 相比，硼替佐米对 PSMD2 具有更强的亲和力。体外和体内实验证明了硼替佐米对具有不同驱动突变或具有酪氨酸激酶抑制剂耐药性的 NSCLC 的抑制作用。综上所述，硼替佐米可以靶向PSMD2、PSMB1和PSMB5抑制细胞周期检查点的蛋白酶体降解，从而阻断NSCLC细胞增殖，是NSCLC患者潜在的可选药物。©2023。作者。

The drug therapy for non-small cell lung cancer (NSCLC) have always been issues of poisonous side effect, acquired drug resistance and narrow applicable population. In this study, we built a novel network analysis method (difference- correlation- enrichment- causality- node), which was based on the difference analysis, Spearman correlation network analysis, biological function analysis and Bayesian causality network analysis to discover new therapeutic target of NSCLC in the sequencing data of BEAS-2B and 7 NSCLC cell lines. Our results showed that, as a proteasome subunit coding gene in the central of cell cycle network, PSMD2 was associated with prognosis and was an independent prognostic factor for NSCLC patients. Knockout of PSMD2 inhibited the proliferation of NSCLC cells by inducing cell cycle arrest, and exhibited marked increase of cell cycle blocking protein p21, p27 and decrease of cell cycle driven protein CDK4, CDK6, CCND1 and CCNE1. IPA and molecular docking suggested bortezomib has stronger affinity to PSMD2 compared with reported targets PSMB1 and PSMB5. In vitro and In vivo experiments demonstrated the inhibitory effect of bortezomib in NSCLC with different driven mutations or with tyrosine kinase inhibitors resistance. Taken together, bortezomib could target PSMD2, PSMB1 and PSMB5 to inhibit the proteasome degradation of cell cycle check points, to block cell proliferation of NSCLC, which was potential optional drug for NSCLC patients.© 2023. The Author(s).