Department of Cardiology, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou Central Hospital, Zhejiang, 313000, China.
The First Clinical Medical College, Wenzhou Medical University, Zhejiang, 325000, China.
Biochem Biophys Res Commun. 2024 Mar 12;700:149582. doi: 10.1016/j.bbrc.2024.149582. Epub 2024 Jan 25.
Doxorubicin (DOX) is a widely used antitumor drug, but its clinical applicability is hampered by the unfortunate side effect of DOX-induced cardiotoxicity (DIC). In our current study, we retrieved three high-throughput sequencing datasets related to DIC from the Gene Expression Omnibus (GEO) datasets. We conducted differential analysis using R (DESeq2) to pinpoint differentially expressed genes (DEGs, and identified 11 genes that were consistently altered in both the control and DOX-treated groups. Notably, our Random Forest analysis of these three GEO datasets highlighted the significance of nuclear receptor subfamily 4 group A member 1 (NR4A1) in the context of DIC. The DOX-induced mouse model and cell model were used for the in vivo and in vitro studies to reveal the role of NR4A1 in DIC. We found that silencing NR4A1 by adeno-associated virus serotype 9 (AAV9) contained shRNA in vivo alleviated the DOX-induced cardiac dysfunction, cardiomyocyte injury and fibrosis. Mechanistically, we found NR4A1 silencing was able to inhibit DOX-induced the cleavage of NLRP3, IL-1β and GSDMD in vivo. Further in vitro studies have shown that inhibition of NR4A1 suppressed DOX-induced cytotoxicity and oxidative stress through the same molecular mechanism. We prove that NR4A1 plays a critical role in DOX-induced cardiotoxicity by inducing pyroptosis via activation of the NLRP3 inflammasome, and it might be a promising therapeutic target for DIC.
多柔比星（DOX）是一种广泛应用的抗肿瘤药物，但由于其导致的心脏毒性（DIC）的不幸副作用，其临床适用性受到限制。在我们目前的研究中，我们从基因表达综合数据库（GEO）中检索了三个与 DIC 相关的高通量测序数据集。我们使用 R（DESeq2）进行差异分析，以确定差异表达基因（DEGs），并鉴定出 11 个在对照组和 DOX 处理组中均发生改变的基因。值得注意的是，我们对这三个 GEO 数据集的随机森林分析突出了核受体亚家族 4 组 A 成员 1（NR4A1）在 DIC 中的重要性。我们使用 DOX 诱导的小鼠模型和细胞模型进行体内和体外研究，以揭示 NR4A1 在 DIC 中的作用。我们发现，体内用腺相关病毒血清型 9（AAV9）携带 shRNA 沉默 NR4A1 可减轻 DOX 诱导的心脏功能障碍、心肌细胞损伤和纤维化。从机制上讲，我们发现 NR4A1 沉默能够抑制体内 DOX 诱导的 NLRP3、IL-1β 和 GSDMD 的切割。进一步的体外研究表明，通过相同的分子机制，抑制 NR4A1 可抑制 DOX 诱导的细胞毒性和氧化应激。我们证明，NR4A1 通过激活 NLRP3 炎性小体诱导细胞焦亡，在 DOX 诱导的心脏毒性中发挥关键作用，并且可能是 DIC 的一个有前途的治疗靶点。
