The role of heme in sepsis induced Kupffer cell PANoptosis and senescence.

Summary

Heme drives mitochondrial damage that triggers Kupffer cell PANoptosis and senescence in sepsis via PLC-γ–dependent translocation of c-GSDMD to mitochondria and activation of cGAS-STING. Pharmacologic PLC-γ inhibition and hemopexin reduced mitochondrial injury, cell death, senescence, bacterial burden, and mortality in both young and aged mice.

Key Findings

• Elevated heme in CLP sepsis correlates with Kupffer cell loss, increased bacterial burden, and higher mortality.
• Heme activates PLC-γ, driving c-GSDMD translocation to mitochondria, pore formation, mitochondrial dysfunction, mtDNA release, PANoptosis, and cGAS-STING–mediated senescence.
• PLC-γ inhibition and hemopexin reduce Kupffer cell death and senescence, enhance bacterial clearance, and improve survival in young and aged mice.

Clinical Implications

Supports testing hemopexin and PLC-γ inhibitors as adjunctive therapies in hemolysis-associated sepsis and prompts biomarker development (plasma heme, c-GSDMD, mtDNA) for patient stratification.

Limitations

• Preclinical mouse study; human validation and clinical dosing/ timing remain unknown.
• Potential off-target effects of PLC-γ inhibition require safety assessment.

Future Directions

Evaluate hemopexin and PLC-γ inhibitors in large-animal sepsis models and early-phase clinical trials; develop heme/c-GSDMD/mtDNA biomarker-guided enrichment strategies.