Integrated multi-omics deciphers sepsis immune dysregulation: a dual-pathway targeted small-molecule therapy improves survival and ameliorates multi-organ dysfunction.

Sepsis is a life-threatening organ dysfunction syndrome with persistently high global mortality, driven by dysregulated host immune response. Existing single-target therapies fail to simultaneously address hyperinflammation and impaired tissue repair, leading to limited clinical efficacy and repeated translational failures. Integrated multi-omics datasets (scRNA-seq, miRNA-seq, blood/lung RNA-seq) delineated immune cell dynamics and dysregulated pathways in sepsis. Guided by omics findings, we designed two small-molecule combinations (C1, C2) targeting the identified pathways. Their efficacy and mechanism were validated in in vitro and in vivo sepsis models. Septic patients showed a hallmark immune remodeling signature: expansion of pro-inflammatory myeloid cells (neutrophils, monocytes) and depletion of protective lymphoid cells (B cells, NK cells). A dual-pathway small-molecule combination C2 targeting inflammatory cascades and Hippo/Wnt regenerative pathways, exerted significant synergistic therapeutic effects. It robustly rebalanced systemic and organ-specific inflammation (suppressed Il1b, Il6, Nos2, Tnfa; elevated Il10, Arg1, Tgfb, Nos3) in vitro and in vivo, ameliorated multi-organ injury, and improved 7-day survival in septic mice from 20% (untreated) to 70%. Single-compound control experiments confirmed that the enhanced efficacy of C2 stems from dual-pathway synergy, not individual components. This study revealed immune dysregulation as the core pathogenesis of sepsis. The C2 combination simultaneously mitigates hyperinflammation and promotes tissue repair, providing a novel, mechanism-driven, and clinically translatable combination strategy for sepsis management.