ANXA2 promotes NLRP3 inflammasome activation and neuronal pyroptosis after intracerebral hemorrhage

By
Qingyuan Wu
Yuetao Wen
Yiqing Shen
XiangYu Chen
WenSong Yang
Limin Ma
Peng Xie
May 26, 2026

Frontiers In Immunology

Overview

This study identifies Annexin A2 (ANXA2) as a key regulator of NLRP3 inflammasome activation and neuronal pyroptosis following intracerebral hemorrhage (ICH). Silencing ANXA2 significantly improved neurological function and reduced brain injury, highlighting its potential as a therapeutic target in ICH management.

Background

Intracerebral hemorrhage (ICH) is a severe stroke type with high mortality and long-term disability rates. The secondary brain injury mechanisms following ICH, particularly those involving neuroinflammation and pyroptosis, remain poorly understood. Understanding these pathways is crucial for developing effective treatments for ICH, as current pharmacological options are limited.

Data Highlights

Measurement	Outcome
NLRP3 inflammasome activation	Reduced with ANXA2 silencing
GSDMD cleavage	Decreased with ANXA2 silencing
IL-1β/IL-18 secretion	Significantly reduced with ANXA2 silencing
Neurological function	Improved with ANXA2 silencing
Brain injury	Alleviated with ANXA2 silencing

Key Findings

ANXA2 was identified as a hub protein upregulated after ICH.
Co-immunoprecipitation showed a direct association between ANXA2 and NLRP3.
Silencing ANXA2 led to reduced activation of the NLRP3 inflammasome.
ANXA2 silencing decreased GSDMD cleavage and IL-1β/IL-18 secretion.
Improved neurological function was observed following ANXA2 silencing.
ANXA2 plays a critical role in the neuronal–immune convergence mechanism in ICH.

Clinical Implications

Targeting ANXA2 may provide a novel therapeutic approach to mitigate neuronal pyroptosis and neuroinflammation in ICH. Understanding the ANXA2–NLRP3 pathway could lead to the development of new strategies to improve outcomes for patients suffering from ICH.

Conclusion

The findings of this study underscore the importance of ANXA2 in the regulation of neuronal pyroptosis following ICH. Further exploration of this pathway may yield significant insights into potential therapeutic interventions for ICH.