Table_1_SDF4 Is a Prognostic Factor for 28-Days Mortality in Patients With Sepsis via Negatively Regulating ER Stress.xlsx

Sepsis is a heterogeneous syndrome induced by infection and results in high mortality. Even though more than 100 biomarkers for sepsis prognosis were evaluated, prediction of patient outcomes in sepsis continues to be driven by clinical signs because of unsatisfactory specificity and sensitivity of these biomarkers. This study aimed to elucidate the key candidate genes involved in sepsis response and explore their downstream effects based on weighted gene co-expression network analysis (WGCNA). The dataset GSE63042 with sepsis outcome information was obtained from the Gene Expression Omnibus (GEO) database and then consensus WGCNA was conducted. We identified the hub gene SDF4 (stromal cell derived factor 4) from the M6 module, which was significantly associated with mortality. Subsequently, two datasets (GSE54514 and E-MTAB-4421) and cohort validation (n=89) were performed. Logistic regression analysis was used to build a prediction model and the combined score resulting in a satisfactory prognosis value (area under the ROC curve=0.908). The model was subsequently tested by another sepsis cohort (n=70, ROC= 0.925). We next demonstrated that endoplasmic reticulum (ER) stress tended to be more severe in patients PBMCs with negative outcomes compared to those with positive outcomes and SDF4 was related to this phenomenon. In addition, our results indicated that adenovirus-mediated Sdf4 overexpression attenuated ER stress in cecal ligation and puncture (CLP) mice lung. In summary, our study indicates that incorporation of SDF4 can improve clinical parameters predictive value for the prognosis of sepsis, and decreased expression levels of SDF4 contributes to excessive ER stress, which is associated with worsened outcomes, whereas overexpression of SDF4 attenuated such activation.

败血症是一种由感染引起的异质症候群，其死亡率极高。尽管已评估了超过100种败血症预后生物标志物，但由于这些生物标志物的特异性和敏感性尚不令人满意，败血症患者结局的预测仍然主要依赖于临床体征。本研究旨在阐明参与败血症反应的关键候选基因，并基于加权基因共表达网络分析（WGCNA）探讨其下游效应。数据集GSE63042，包含败血症结局信息，来源于基因表达综合数据库（GEO），随后进行了共识WGCNA分析。我们从M6模块中鉴定出枢纽基因SDF4（间质细胞衍生因子4），其与死亡率显著相关。随后，进行了两个数据集（GSE54514和E-MTAB-4421）和队列验证（n=89）。利用逻辑回归分析构建预测模型，并得到令人满意的预后值（ROC曲线下面积=0.908）。该模型随后通过另一个败血症队列（n=70，ROC=0.925）进行测试。我们进一步证明了，与阳性结果的患者相比，阴性结果的患者外周血单个核细胞（PBMCs）中的内质网（ER）应激程度往往更严重，且SDF4与这种现象相关。此外，我们的研究结果还表明，腺病毒介导的Sdf4过表达减轻了结扎穿孔（CLP）小鼠肺部的ER应激。总之，本研究表明，SDF4的整合可以提高败血症预后的临床参数预测价值，而SDF4表达水平的降低则导致过度ER应激，这与不良结局相关，而SDF4的过表达则减轻了这种激活。