Cross-Species Transcriptomic Triangulation and Exploratory LINCS L1000 Reversal in Sepsis-associated ARDS: Integrating Human Blood (GSE66890, GSE32707) and Murine Lung Endothelium (GSE169532)

Background: Sepsis-associated acute respiratory distress syndrome (ARDS) lacks validated host-directed pharmacotherapies capable of reversing pulmonary microvascular endothelial injury. Aims: To integrate human whole-blood ARDS-versus-sepsis transcriptomes with murine pulmonary endothelial responses to prioritise exploratory small-molecule reversal candidates. Study Design: Integrative cross-species transcriptomic meta-analysis and connectivity-reversal pharmacoinformatics study. Place and Duration of Study: CMHC Research Center, Palembang, and ANC Medical Center, Jakarta, Indonesia. Methodology: Human blood cohorts (GSE66890, n = 57 [29 ARDS, 28 sepsis; 18,085 genes]; GSE32707 Day 0, n = 48 [18 ARDS, 30 sepsis; 20,748 genes]; N = 105) were analysed via empirical Bayes limma and DerSimonian–Laird meta-analysis across 17,171 shared genes with reciprocal replication auditing. Estimates were triangulated with murine cecal ligation and puncture lung capillary (capEC, n = 6) and postcapillary venular (PCV, n = 6) endothelial RNA-seq (GSE169532, N = 12) via 1:1 orthology, L1000CDS2, 20 API and 10,000 Monte Carlo random controls, ChEMBL v34, and STRING v12.5. Results: No gene reached FDR < 0.05 in either human cohort alone (80 reached FDR < 0.10 in GSE66890; 0 in GSE32707; Spearman ρ = 0.072; concordant sign 9,111/17,171 [53.06%]). Meta-analysis identified 11 genes at FDR < 0.05; only PIM1 (log2FCmeta = 0.555, SE = 0.123, FDR = 0.019) was concordantly upregulated in murine capEC (log2FC = 1.345, FDR = 0.004) and PCV (log2FC = 1.548, FDR = 0.016). A 38-gene barrier panel showed no enrichment (Mann–Whitney p = 0.513). L1000CDS2 prioritised selumetinib (score = 0.1176 [0.118], A375, 80.0 µM; pemp = 0.0476; pMC = 0.0018), geldanamycin, and AS605240 across three specifications, though none ranked in the GSE32707 top 50. Conclusion: Cross-species integration identifies PIM1 as a convergent node and prioritizes selumetinib, geldanamycin, and AS605240 as preclinical candidates requiring multi-stage experimental and clinical confirmation.