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Therapeutic Targets for Sepsis: Multicenter Proteome-Wide Analyses and Experimental Validation
Bingyang Liu1, Yuhong Jin1, Yi Ding1
1Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo 315040, China.
Journal of Proteome Research
|June 3, 2025
Summary
This study identifies three proteins—dual specificity phosphatase 13 (DUSP13), inhibin beta C chain (INHBC), and toll-like receptor 1 (TLR1)—as potential therapeutic targets for sepsis. Genetic and experimental data support their causal links to sepsis risk and altered levels in patients.
Area of Science:
- Genetics
- Proteomics
- Immunology
Background:
- Sepsis is a critical illness with high mortality, necessitating novel therapeutic strategies.
- Identifying causal protein targets is crucial for developing effective sepsis treatments.
Purpose of the Study:
- To identify proteins causally associated with sepsis risk using a proteome-wide Mendelian randomization approach.
- To validate potential therapeutic targets through genetic, phenotypic, and experimental evidence.
Main Methods:
- Proteome-wide Mendelian randomization analysis across large genetic cohorts (FinnGen, UKB-PPP, deCODE).
- Prioritization of proteins using stringent statistical criteria (FDR <0.05 and p <0.05).
- Colocalization, phenome-wide association studies (PheWAS), and ELISA validation in sepsis patients.
Main Results:
- Three proteins—DUSP13, INHBC, and TLR1—showed strong genetic evidence for causal association with sepsis.
- PheWAS indicated broader disease links for DUSP13 and TLR1; INHBC was identified as druggable.
- ELISA confirmed elevated DUSP13 and INHBC, and reduced TLR1 serum levels in sepsis patients.
Conclusions:
- DUSP13, INHBC, and TLR1 are promising therapeutic targets for sepsis.
- Genetic, phenotypic, and experimental data collectively support these proteins' roles in sepsis pathogenesis.
- Targeting these proteins may offer novel treatment avenues for sepsis.
