直肠癌（RC）占结直肠癌（CRC）的三分之一，其中40％为局部晚期直肠癌（LARC）。新辅助放化疗（nCRT）与仅手术或术后治疗相比显著降低了局部复发率。然而，在nCRT后，多达40-60％的患者出现严重的病理反应，仅约20％的患者达到病理完全缓解。在这种情况下，迫切需要确定新的预测nCRT肿瘤反应的指标，以降低LARC死亡率，并将反应差的患者从不必要治疗中挽救出来。因此，我们通过将基因和microRNA表达数据集与LARC患者的蛋白质组学数据相结合，开发了一个以七个中心基因为核心的网络，这些基因可能与nCRT反应有关。在一个独立的验证队列中，我们证实了NFKB1、TRAF6和STAT3的差异表达与nCRT反应相关。此外，功能富集分析还揭示了这些基因与癌症和炎症的代表性密切相关，其功能障碍可能会对LARC患者对nCRT的反应产生因果影响。此外，通过构建转录因子模块网络，我们假设POU2F3基因具有保护作用，可用作LARC患者的新药靶标。最后，我们鉴定并在体外测试了一种组蛋白去乙酰化酶抑制剂entinostat，该药物可与经典治疗方案结合使用，以设计更有效的LARC治疗策略。本文受版权保护。版权所有。

Rectal cancer (RC) accounts for one-third of colorectal cancers (CRC), and 40% of these are locally advanced rectal cancers (LARC). The use of neoadjuvant chemoradiotherapy (nCRT) significantly reduces the rate of local recurrence compared to adjuvant therapy or surgery alone. However, after nCRT, up to 40-60% of patients show a poor pathological response, while only about 20% achieve a pathological complete response. In this scenario, the identification of novel predictors of tumor response to nCRT is urgently needed to reduce LARC mortality and to spare poorly responding patients from unnecessary treatments. Therefore, by combining gene and microRNA expression datasets with proteomic data from LARC patients, we developed an integrated network centered on seven hub-genes putatively involved in the response to nCRT. In an independent validation cohort of LARC patients, we confirmed that differential expression of NFKB1, TRAF6 and STAT3 is correlated with the response to nCRT. In addition, the functional enrichment analysis also revealed that these genes are strongly related to hallmarks of cancer and inflammation, whose dysfunction may causatively affect LARC patient's response to nCRT. Furthermore, by constructing the transcription factor-module network, we hypothesized a protective role of POU2F3 gene, which could be used as a new drug target in LARC patients. Finally, we identified and tested in vitro entinostat, a histone deacetylase inhibitor, as a chemical compound that could be combined with a classical therapeutic regimen in order to design more efficient therapeutic strategies in LARC management.This article is protected by copyright. All rights reserved.