HDAC3 Mediates Hippocampal Microglial Pyroptosis Via the STING/NLRP3 Pathway and Contributes To Cognitive Impairment in Sepsis-Associated Encephalopathy.

Summary

Using CLP-induced sepsis models with microglia-specific genetic manipulation and a selective HDAC3 inhibitor, the study shows that microglial HDAC3 activates pyroptosis via STING/NLRP3, driving oxidative stress, neural dysfunction, and cognitive deficits. Pharmacologic inhibition with RGFP966 mitigated these effects, positioning HDAC3 as a therapeutic target in sepsis-associated encephalopathy.

Key Findings

• Microglial HDAC3 activates pyroptosis via STING/NLRP3, increasing oxidative stress and impairing neural activity in CLP-induced sepsis.
• Microglia-specific overexpression of HDAC3 reproduces cognitive and pathological deficits characteristic of SAE.
• The selective HDAC3 inhibitor RGFP966 attenuates pyroptosis, inflammatory signaling, and cognitive deficits when administered for 14 days.

Clinical Implications

While preclinical, targeting microglial HDAC3 could inform future trials of HDAC3 inhibitors or epigenetic modulators to prevent or treat sepsis-associated encephalopathy, particularly if effective in delayed treatment windows.

Limitations

• Preemptive dosing started 2 hours before CLP may overestimate translatability to clinical settings.
• Sample size and sex balance were not specified; human validation is lacking.

Future Directions

Test delayed/post-insult HDAC3 inhibition, validate HDAC3/STING/NLRP3 signaling in human biospecimens, and assess target engagement and cognitive outcomes in early phase clinical trials.