Hexokinase 2 promotes ISGylation of Acyl-CoA synthetase long-chain family member 4 in sepsis-induced microglia cells.

Summary

This study identifies HK2 as a metabolic-immune regulator in sepsis-associated encephalopathy, promoting NLRP3 activation and lipid droplet accumulation in microglia. Mechanistically, HK2 enhances ISG15-dependent ISGylation of ACSL4; HK2 or ISG15 knockdown reduces ACSL4 and inflammatory signaling, nominating HK2 as a therapeutic target.

Key Findings

• HK2 is upregulated in LPS-stimulated BV2 microglia and hippocampus of CLP-induced septic mice, correlating with inflammatory signaling.
• HK2 downregulation reduces NLRP3 activation and diminishes lipid droplet accumulation in microglia.
• HK2 knockdown decreases ISG15-dependent ISGylation of ACSL4; siISG15 lowers ACSL4 expression in LPS-stimulated microglia.

Clinical Implications

While preclinical, targeting HK2 or modulating ISGylation could attenuate neuroinflammation in sepsis-associated encephalopathy; translational validation is needed.

Limitations

• Use of BV2 cell line and male mice; primary human microglia/tissue validation lacking
• Limited causal rescue experiments to directly link ACSL4 ISGylation changes to phenotypes

Future Directions

Validate HK2–ISG15–ACSL4 axis in primary human microglia and patient tissues; test pharmacologic HK2 inhibition and cell type–specific modulation in sepsis models.