Frontiers in cell and developmental biology · 2026
Concurrent activation of multiple programmed cell death pathways predicts 28-day mortality in pediatric sepsis: a retrospective PICU cohort study with differential sedative agent use between survivors and non-survivors.
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Fu Bingfeng, Sun Yingchao, Zhang Xifeng
Аннотация
OBJECTIVE: To systematically characterize the expression profiles of biomarkers associated with multiple programmed cell death (PCD) pathways-including apoptosis, pyroptosis, necroptosis, and ferroptosis-in pediatric intensive care unit (PICU) patients with sepsis, elucidate their associations with organ dysfunction severity and clinical prognosis, and identify independent predictors of 28-day all-cause mortality in children.
METHODS: A retrospective cohort study was conducted on 208 pediatric sepsis patients (aged 1 month to 18 years) admitted to the PICU of Jingzhou First People's Hospital between January 2021 and December 2023. Based on 28-day survival outcomes, patients were divided into a survival group (n = 148) and a death group (n = 60). Plasma biomarkers for apoptosis (caspase-3, caspase-9, Bcl-2, Bax), pyroptosis (NLRP3, caspase-1, GSDMD, IL-1β, IL-18), necroptosis (RIPK1, RIPK3, MLKL), ferroptosis (GPX4, ferritin, MDA, 4-HNE), and damage-associated molecular patterns (DAMPs: HMGB1, HSP70, S100A8/A9) were measured within 24 h of PICU admission. ROC analysis, Kaplan-Meier survival analysis, and Cox proportional hazards regression were employed for prognostic evaluation.
RESULTS: The 28-day mortality rate was 28.8% (60/208). Non-survivors demonstrated significantly elevated NLRP3, caspase-1, GSDMD, IL-18, RIPK3, MLKL, HMGB1, ferritin, and MDA, and significantly lower GPX4 and Bcl-2/Bax ratio compared to survivors (all P < 0.001). NLRP3 demonstrated the highest individual predictive value (AUC = 0.836), and the combined biomarker panel (NLRP3+GPX4+HMGB1) substantially outperformed pSOFA score alone (AUC = 0.896 vs. 0.786). Multivariate Cox regression identified NLRP3 >2.45 ng/mL (HR = 2.847, 95%CI: 1.682-4.819), GPX4 <12.3 ng/mL (HR = 2.234, 95%CI: 1.458-3.425), HMGB1 >15.6 ng/mL (HR = 1.856, 95%CI: 1.142-3.015), and pSOFA score >8 (HR = 1.672, 95%CI: 1.089-2.567) as independent predictors of 28-day mortality (C-index = 0.821).
CONCLUSION: Multiple PCD pathways are concurrently activated in pediatric sepsis, with NLRP3-driven pyroptosis and GPX4-deficient ferroptosis as the strongest independent mortality predictors. From a pediatric anesthesiology perspective, anesthetic agents with documented anti-pyroptotic or anti-ferroptotic properties-including dexmedetomidine and propofol-may represent adjunctive organ-protective strategies. Combined PCD biomarker profiling provides additive prognostic value beyond conventional severity scores and identifies mechanistically distinct therapeutic targets.
METHODS: A retrospective cohort study was conducted on 208 pediatric sepsis patients (aged 1 month to 18 years) admitted to the PICU of Jingzhou First People's Hospital between January 2021 and December 2023. Based on 28-day survival outcomes, patients were divided into a survival group (n = 148) and a death group (n = 60). Plasma biomarkers for apoptosis (caspase-3, caspase-9, Bcl-2, Bax), pyroptosis (NLRP3, caspase-1, GSDMD, IL-1β, IL-18), necroptosis (RIPK1, RIPK3, MLKL), ferroptosis (GPX4, ferritin, MDA, 4-HNE), and damage-associated molecular patterns (DAMPs: HMGB1, HSP70, S100A8/A9) were measured within 24 h of PICU admission. ROC analysis, Kaplan-Meier survival analysis, and Cox proportional hazards regression were employed for prognostic evaluation.
RESULTS: The 28-day mortality rate was 28.8% (60/208). Non-survivors demonstrated significantly elevated NLRP3, caspase-1, GSDMD, IL-18, RIPK3, MLKL, HMGB1, ferritin, and MDA, and significantly lower GPX4 and Bcl-2/Bax ratio compared to survivors (all P < 0.001). NLRP3 demonstrated the highest individual predictive value (AUC = 0.836), and the combined biomarker panel (NLRP3+GPX4+HMGB1) substantially outperformed pSOFA score alone (AUC = 0.896 vs. 0.786). Multivariate Cox regression identified NLRP3 >2.45 ng/mL (HR = 2.847, 95%CI: 1.682-4.819), GPX4 <12.3 ng/mL (HR = 2.234, 95%CI: 1.458-3.425), HMGB1 >15.6 ng/mL (HR = 1.856, 95%CI: 1.142-3.015), and pSOFA score >8 (HR = 1.672, 95%CI: 1.089-2.567) as independent predictors of 28-day mortality (C-index = 0.821).
CONCLUSION: Multiple PCD pathways are concurrently activated in pediatric sepsis, with NLRP3-driven pyroptosis and GPX4-deficient ferroptosis as the strongest independent mortality predictors. From a pediatric anesthesiology perspective, anesthetic agents with documented anti-pyroptotic or anti-ferroptotic properties-including dexmedetomidine and propofol-may represent adjunctive organ-protective strategies. Combined PCD biomarker profiling provides additive prognostic value beyond conventional severity scores and identifies mechanistically distinct therapeutic targets.