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

<h4>Introduction</h4>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.<h4>Methods</h4>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 <i>in vitro</i> and <i>in vivo</i> sepsis models.<h4>Results</h4>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 <i>Il1b</i>, <i>Il6</i>, <i>Nos2</i>, <i>Tnfa</i>; elevated <i>Il10</i>, <i>Arg1</i>, <i>Tgfb</i>, <i>Nos3</i>) <i>in vitro</i> and <i>in vivo</i>, 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.<h4>Discussion</h4>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.