Comprehensive analysis of metabolism-related genes in sepsis reveals metabolic-immune heterogeneity and highlights GYG1 as a potential therapeutic target.

Summary

An integrative analysis of bulk and single-cell transcriptomes defined an immune-metabolic risk score in sepsis and identified GYG1 as the strongest predictor enriched in myeloid cells. High-risk patients displayed neutrophil-dominant, lymphocyte-suppressed profiles; LNP-siRNA targeting of GYG1 reduced myeloid glycogen availability and inflammatory output in preclinical models.

Key Findings

• Two sepsis subgroups defined by metabolism-related genes showed divergent immune infiltration; high-risk was neutrophil-dominant and lymphocyte-suppressed.
• A five-gene metabolic risk score (ALPL, CYP1B1, GYG1, OLAH, VNN1) predicted outcomes and was externally validated.
• GYG1 had the strongest predictive performance and was highly expressed in monocytes, neutrophils, and proliferating myeloid cells.
• High-risk patients exhibited intensified monocyte–dendritic cell interactions and enrichment of neutrophil degranulation programs.
• LNP-siRNA targeting GYG1 reduced glycogen availability and inflammatory output in myeloid cells, improving disease outcomes in preclinical evaluation.

Clinical Implications

A metabolic risk score may guide prognostication and trial stratification; GYG1 inhibition represents a candidate immunometabolic therapy pending validation of efficacy and safety in humans.

Limitations

• Abstract lacks details on experimental models, sample sizes, and specific clinical endpoints linked to the risk score.
• Translational applicability of GYG1 inhibition remains to be established in humans; potential overfitting cannot be excluded.

Future Directions

Prospective validation of the risk score across centers; mechanistic dissection of GYG1 in human myeloid cells; early-phase trials assessing safety and pharmacodynamics of GYG1-targeted approaches.