Estrogen receptor β deficiency increases susceptibility to sepsis through metabolic reprogramming-induced macrophage pyroptosis.

Summary

Human and animal data show ERβ expression is reduced in sepsis and its deficiency drives macrophage pyroptosis via enhanced fatty acid oxidation, increased acetyl-CoA, and Stoml2 K221 acetylation. Genetic disruption of this acetylation site rescues mitochondrial function and improves survival in septic mice, identifying ERβ deficiency as a susceptibility factor.

Key Findings

• ERβ expression is significantly reduced in peripheral blood of sepsis patients and inversely correlates with disease severity.
• ERβ deficiency enhances fatty acid oxidation, elevates acetyl-CoA, and promotes Stoml2 K221 acetylation, triggering mitochondrial dysfunction and macrophage pyroptosis.
• Mutating Stoml2 K221 mitigates pyroptosis-related dysfunction and improves survival in septic mice, implicating ERβ deficiency as a genetic susceptibility factor.

Clinical Implications

ERβ expression could serve as a biomarker for sepsis susceptibility or risk stratification. Selective ERβ modulators or interventions targeting FAO/acetylation pathways may prevent macrophage pyroptosis and improve outcomes, warranting translational studies.

Limitations

• Clinical causality and generalizability are not established; human genetic variation in ESR2 was not detailed.
• Therapeutic translatability of ERβ modulation and safety profiles require dedicated preclinical and clinical studies.

Future Directions

Validate ERβ as a prognostic/diagnostic biomarker, test selective ERβ modulators or FAO/acetylation pathway inhibitors, and examine sex-specific and genotype–phenotype effects in diverse sepsis cohorts.