Exploratory serum proteomics and independent validation identify SLC3A2 as a candidate biomarker associated with the near-death state

Abstract Accurate prognostication in critically ill patients remains a central challenge. This study aimed to explore serum proteomic changes associated with the near-death state and to evaluate candidate biomarkers. We conducted a two-phase study, beginning with data-independent acquisition mass spectrometry (DIA-MS) on a discovery cohort of patients with acute cerebral infarction ( n = 6). Candidate biomarkers were then evaluated via ELISA in an independent, heterogeneous cohort of critically ill neurological patients ( n = 60). Exploratory proteomic profiling suggested broad molecular differences between the near-death and stable states, although no protein remained statistically significant after multiple-testing correction in the small discovery cohort. Candidate prioritization nevertheless identified Solute Carrier Family 3 Member 2 (SLC3A2) for downstream validation. Serum SLC3A2 concentrations were higher in near-death patients than in stable controls ( P = 0.008) and showed moderate discrimination between the two states (AUC = 0.722). After adjustment for APACHE II, the association of SLC3A2 with ND status was not statistically significant, and its addition did not significantly improve model discrimination. Exploratory decision-curve analysis suggested possible net-benefit advantages over selected threshold probabilities. In conclusion, exploratory proteomic analysis identified nominal protein-level differences associated with the near-death state. SLC3A2 emerged as a candidate biomarker that may complement existing clinical scoring systems, although its incremental and independent prognostic value requires confirmation in larger external cohorts.