ENKD1 modulates innate immune responses through enhanced geranylgeranyl pyrophosphate synthase activity.

Summary

Using screening and mechanistic experiments, the authors identify ENKD1 as a negative regulator of innate immune activation. ENKD1 binds GGPS1 to tune geranylgeranyl diphosphate output, driving RAC1 inactivation and dampening pro-inflammatory signaling; its deletion amplifies septic inflammation in vivo.

Key Findings

• ENKD1 expression decreases upon activation of multiple TLRs.
• ENKD1 deletion enhances innate immune activation and worsens septic inflammation in vivo.
• ENKD1 physically interacts with GGPS1 and modulates its enzymatic activity to influence geranylgeranyl diphosphate production.
• Through this axis, RAC1 is inactivated, suppressing downstream pro-inflammatory signaling.

Clinical Implications

Although preclinical, the ENKD1–GGPS1 pathway suggests druggable nodes (e.g., prenylation enzymes) to attenuate septic hyperinflammation while potentially preserving host defense. Biomarker development around ENKD1 expression/activity may help stratify inflammatory phenotypes.

Limitations

• Preclinical study; human validation (cells, tissues, patients) is lacking.
• Quantitative sample sizes and replication across models are not detailed in the abstract.

Future Directions

Validate ENKD1–GGPS1 signaling in human immune cells and septic patient samples; assess pharmacologic modulation of prenylation; evaluate ENKD1 as a biomarker for inflammatory subphenotypes; test therapeutic targeting in sepsis models with infection control endpoints.