A transcriptome-based risk model in sepsis enables prognostic prediction and drug repositioning
Qiuyue Long,
Hongli Ye,
Shixu Song,
Jiwei Li,
Jing Wu,
Jingsong Mao,
Ran Li,
Ke Li,
Zhancheng Gao,
Yali Zheng
Affiliations
Qiuyue Long
Department of Respiratory, Critical Care and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China; Institute of Chest and Lung Diseases, Xiamen University, Xiamen 361101, China
Hongli Ye
Department of Respiratory, Critical Care and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China; Institute of Chest and Lung Diseases, Xiamen University, Xiamen 361101, China
Shixu Song
Department of Respiratory, Critical Care and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China; Institute of Chest and Lung Diseases, Xiamen University, Xiamen 361101, China
Jiwei Li
Department of Respiratory, Critical Care and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China; Institute of Chest and Lung Diseases, Xiamen University, Xiamen 361101, China
Jing Wu
Department of Respiratory, Critical Care and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China; Institute of Chest and Lung Diseases, Xiamen University, Xiamen 361101, China
Jingsong Mao
Department of Vascular Intervention, Guilin Medical College Affiliated Hospital, Guilin Medical College, Guilin 541000, China
Ran Li
Department of Respiratory and Critical Care Medicine, Peking University People’s Hospital, Beijing 100044, China
Ke Li
Department of Critical Care Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China; Corresponding author
Zhancheng Gao
Department of Respiratory, Critical Care and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China; Institute of Chest and Lung Diseases, Xiamen University, Xiamen 361101, China; Department of Respiratory and Critical Care Medicine, Peking University People’s Hospital, Beijing 100044, China; Corresponding author
Yali Zheng
Department of Respiratory, Critical Care and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China; Institute of Chest and Lung Diseases, Xiamen University, Xiamen 361101, China; Corresponding author
Summary: Septic management presented a tremendous challenge due to heterogeneous host responses. We aimed to develop a risk model for early septic stratification based on transcriptomic signature. Here, we combined genes OLAH, LY96, HPGD, and ABLIM1 into a prognostic risk score model, which demonstrated exceptional performance in septic diagnosis (AUC = 0.99–1.00) and prognosis (AUC = 0.61–0.70), outperforming that of Mars and SRS endotypes. Also, the model unveiled immunosuppressive status in high-risk patients and a poor response to hydrocortisone in low-risk individuals. Single-cell transcriptome analysis further elucidated expression patterns and effects of the four genes across immune cell types, illustrating integrated host responses reflected by this model. Upon distinct transcriptional profiles of risk subgroups, we identified fenretinide and meloxicam as therapeutic agents, which significantly improved survival in septic mice models. Our study introduced a risk model that optimized risk stratification and drug repurposing of sepsis, thereby offering a comprehensive management approach.
