Weaning from venoarterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiogenic shock remains a major challenge in intensive care practice. Previous studies have explored cytokines and chemokines as potential predictors of weaning outcomes, often using limited biomarker panels and relatively small cohorts. We therefore evaluated whether patterns of soluble circulating factors could predict successful ECMO weaning in patients with cardiogenic shock. Additional tools that provide complementary biological information may improve early risk stratification during the weaning process. In this retrospective cohort study, we analyzed 247 adult patients with cardiogenic shock who received VA-ECMO support. Patients were randomly allocated to a derivation cohort (70%) and an internal validation cohort (30%). Plasma levels of 14 differentially expressed soluble factors were measured within the Day1 of ECMO support, and a composite differentially expressed soluble factors score (DeSF-Score) was constructed. The predictive performance of DeSF-Score components for successful ECMO weaning was assessed and compared with conventional clinical parameters. Patients who failed VA-ECMO weaning exhibited significantly higher DeSF-Scores than those who were successfully weaned ( P < 0.05). The DeSF-Score1, comprising soluble B and T lymphocyte attenuator (sBTLA), IL-10, CCL2, IL-6, and IL-8, demonstrated the strongest discriminatory ability (derivation cohort AUC = 0.725, 95% CI 0.642–0.808) for weaning outcomes and outperformed individual soluble factors. These findings were consistently observed in the internal validation cohort (AUC = 0.708, 95% CI 0.577–0.838). DeSF-Score1 remained independently associated with weaning failure after adjustment for age, Sequential Organ Failure Assessment score, and arterial lactate levels. The addition of DeSF-Score1 provided incremental prognostic value beyond conventional clinical indicators (combined AUC = 0.768, 95% CI 0.700–0.890). The DeSF-Score1, reflecting a systemic immune-inflammatory signature, independently predicts successful weaning from VA-ECMO in patients with cardiogenic shock. This biological score complements established clinical assessments, offering a novel tool for precision risk stratification during the critical phase of ECMO support. Trial Registration This observational study was registered on ClinicalTrials.gov on November 7, 2019 (NCT04158479).
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