An NLRP3 Inflammasome–anchored Astragalus Mechanistic Prior Yields a Mortality-Associated Transcriptomic Signal in ICU Sepsis: a Secondary Analysis with Exploratory Cross-Cohort Assessment

We developed ASTRA, a literature-informed, author-defined Astragalus mechanistic prior, and examined whether integrated and node-level whole-blood transcriptomic scores were associated with 28-day mortality in ICU sepsis. The primary analysis included 479 adults with sepsis from GSE65682; an exploratory cross-cohort directional assessment included 51 Day-1 patients with septic shock from GSE95233. Mean-Z scores were evaluated using age-adjusted logistic regression with false-discovery-rate correction. Sensitivity analyses included singscore, restricted cubic splines, label permutation, leave-one-gene-out analysis, correlations with IL1B and IL6 mRNA, and adjustment for transcriptome-derived myeloid-cell composition. The integrated ASTRA score showed a nominal inverse association with mortality but did not survive false-discovery-rate correction. The NLRP3-related three-gene score showed the strongest association in GSE65682 (OR per 1-SD increase, 0.70; 95