Integrated multi-omics deciphers sepsis immune dysregulation: a dual-pathway targeted small-molecule therapy improves survival and ameliorates multi-organ dysfunction.
Summary
Systems immunology across multiple omics layers mapped sepsis-associated immune remodeling, then rationally informed a dual-pathway small-molecule combination (C2) targeting inflammation and regeneration. In preclinical validation, C2 rebalanced systemic and organ-specific inflammation and improved survival, supporting a translational combination strategy.
Key Findings
- Multi-omics profiling revealed expansion of pro-inflammatory myeloid cells and depletion of lymphoid cells in sepsis.
- A dual-pathway small-molecule combination (C2) targeting inflammatory cascades and Hippo/Wnt regenerative pathways showed synergistic therapeutic effects.
- C2 rebalanced systemic and organ-specific inflammation and improved survival while ameliorating multi-organ dysfunction in preclinical models.
Clinical Implications
Supports clinical testing of combination therapies that concurrently dampen hyperinflammation and promote tissue repair/regeneration in sepsis and potentially sepsis-induced ARDS.
Why It Matters
Bridges discovery and therapy by using multi-omics to rationally design a dual-pathway drug combination that improves survival in sepsis models, addressing persistent translational failures.
Limitations
- Preclinical validation without human clinical trials limits immediate translatability.
- Sample sizes and full mechanistic details are not specified in the abstract.
Future Directions
Advance to phase I/II trials testing dual-pathway combinations; refine patient selection via omics-defined endotypes; assess organ-specific effects including lung injury phenotypes.
Study Information
- Study Type
- Basic/mechanistic research
- Research Domain
- Treatment
- Evidence Level
- V - Preclinical experimental evidence informed by multi-omics
- Study Design
- OTHER