BACKGROUND: Programmed cell death (PCD) has emerged as a pivotal progress in pathogenesis of sepsis, but its role in identification of sepsis has not been fully understood. METHODS: Differentially expressed genes (DEGs) were identified from the GEO database. PCD-related genes were intersected with DEGs, and key PcDEGs were identified through the protein-protein interaction (PPI) network. To pinpoint hub PcDEGs in sepsis, we applied Random Forest (RF), Support Vector Machine (SVM), Extreme Gradient Boosting (XGB), and Generalized Linear Model (GLM) algorithms. Additionally, the expression levels of five hub PcDEGs were validated in single cell RNA sequencing of sepsis patients and peripheral blood mononuclear cells (PBMCs) from a clinical cohort by quantitative real-time PCR (qRT-PCR). LCK expression was further determined by ELISA, and its diagnostic and prognostic value was evaluated using ROC analysis. LCK levels in the cecal ligation and puncture (CLP)-induced sepsis mouse model were assessed by Western blot and Immunofluorescence (IF). Finally, we assessed the regulatory role of LCK in cell apoptosis using flow cytometry and Western blot analysis. RESULTS: 70 PcDEGs were identified by intersecting 690 DEGs and 1254 PCD-related genes. PPI analysis identified top 15 genes based on Degree algorithm. We then identified five hub PcDEGs (LCK, IL10RA, CD3E, CD5 and ITGAM) that could serve as biomarkers through machine learning. As the expressions of LCK, IL10RA, CD3E and CD5 decreased and ITGAM expression was upregulated in septic patients. Consistently, Serum LCK concentration was reduced in septic patients, and the area under the ROC curve (AUC) of LCK was 0.753. Importantly, LCK displayed more pronounced reduction in non-survivors and those with septic shock than survivors and non-shock patients. The AUC for LCK was 0.726 in predicting mortality of septic patients. Moreover, we observed a decrease expression of LCK in the vital organs (liver, lung, spleen, thymus and PBMC) of septic mice model which mirrored observations in septic patients. Finally, we found that inhibiting LCK promoted apoptosis in Jurkat cells. CONCLUSIONS: Our study reveals that PcDEGs are dysregulated in sepsis, and closely related to disease pathology. Our finding provides new insights into clinical identification and outcome prediction of sepsis. Of note, LCK is a new biomarker for diagnosis and prognosis, which might be a potential therapeutic target for the treatment of sepsis.