Multi-omics analysis identifies TBCB as a therapeutic target in sepsis-induced liver injury

BACKGROUND: This study aimed to identify potential therapeutic targets for sepsis and elucidate the underlying molecular mechanisms, with a particular focus on the liver as a key target organ for experimental validation. METHODS: Here, two sequential studies were conducted to uncover and characterize therapeutic targets involved in sepsis-induced liver injury. In Study 1, a proteome-wide Mendelian randomization (MR) analysis was performed using protein quantitative trait loci from deCODE (n = 35 559 Icelanders), UK Biobank (n = 54 219), ARIC (n = 7213 European Americans; n = 1871 African Americans), AGES-Reykjavik (n = 5368 Icelanders), and Fenland (n = 10 708 European ancestry). These datasets were integrated with a sepsis genome-wide association study (GWAS) (FinnGen R12; n = 17 133 cases and 439 048 controls) to identify causal protein candidates. Subsequently, summary-data-based MR was performed. The analysis was based on data from eQTLGen (n = 31 684), GTEx v8 (n = 838 donors), and sepsis GWAS (FinnGen R12; UK Biobank, n = 11 643 cases/474 841 controls). Its goal was to prioritize genes concordant with protein signals. Expression of the candidate was then validated in vivo and in vitro. In Study 2, a metabolite GWAS (n = 8299) was used to investigate metabolic mediation and perform pathway enrichment analysis. Finally, potential small-molecule therapeutics predicted to modulate the prioritized target were identified. RESULTS: Integrated multi-omics analyses identified tubulin-folding cofactor B (TBCB) as a promising therapeutic target for sepsis. Quantitative analyses in both in vivo and in vitro models consistently demonstrated significant upregulation of TBCB during sepsis-induced liver injury. Functional knockdown of TBCB significantly attenuated inflammatory signaling. Mechanistically, TBCB appears to contribute to sepsis progression by modulating intracellular lipid metabolism and metabolic homeostasis. Furthermore, molecular docking and dynamics simulations predicted several small molecules for TBCB, suggesting potential therapeutic value. CONCLUSION: This study identifies TBCB as a central regulator of sepsis pathogenesis, especially in sepsis-induced liver injury. These findings provide novel mechanistic insights and a promising therapeutic target for intervention.