NLRP3-inflammasome–anchored Astragalus mechanistic prior identifies a mortality-associated transcriptomic signal in ICU sepsis
Description
ASTRA is a literature-informed, author-defined Astragalus mechanistic prior developed for interpretable transcriptomic scoring in adult ICU sepsis. PubMed, Embase, and Web of Science searches identified Astragalus-related experimental mechanisms. After deduplication, 4,692 records underwent rule-assisted title/abstract prioritization; the archived 2,222 rows represent candidate bibliographic records retained for source discovery, not full-text-included studies or independently extracted evidence observations. The locked prior contains 10 mechanistic categories, 20 nodes, and 37 representative genes. It was applied to whole-blood transcriptomic data from GSE65682 (479 patients; 114 deaths) and, exploratorily, to GSE95233 (51 Day-1 septic-shock patients; 17 deaths). Integrated and node-level mean-Z scores were evaluated using age-adjusted logistic regression with Benjamini-Hochberg correction across the integrated signature and 11 eligible nodes. Sensitivity analyses included singscore, restricted cubic splines, label permutation, leave-one-gene-out testing, inflammatory-transcript correlations, and MCP-counter/xCell cell-composition adjustment. The integrated ASTRA score was nominally inversely associated with 28-day mortality (OR 0.80 per 1-SD increase, 95% CI 0.65-0.98; q=0.1241). The three-gene NLRP3 node (NLRP3, PYCARD, CASP1) showed the strongest association (OR 0.70, 95% CI 0.57-0.86; q=0.0072). Leave-one-gene-out estimates remained directionally stable (ORs 0.68-0.74). The locked NLRP3 score correlated positively with IL1B and IL6 expression and with MCP-counter monocytic-lineage and neutrophil estimates. Joint MCP-counter adjustment attenuated the association to OR 0.79 (95% CI 0.58-1.06), whereas xCell neutrophil adjustment strengthened it to OR 0.64 (95% CI 0.50-0.83), indicating method-sensitive changes after adjustment for transcriptome-derived composition estimates. In GSE95233, the age-adjusted NLRP3 estimate was directionally concordant but imprecise (OR 0.68, 95% CI 0.37-1.23). ASTRA provides a reproducible framework for translating a botanical mechanistic prior into patient-level transcriptomic scores. The NLRP3-linked finding represents an observational, composition-sensitive whole-blood mRNA state and does not establish protective inflammasome activity, causal pathway regulation, Astragalus efficacy, pharmacological target engagement, clinical-biomarker validity, or formal external validation.