Background Intracerebral hemorrhage (ICH) is a severe form of stroke lacking effective pharmacotherapy, in part because upstream regulators initiating secondary brain injury are not well understood. Pyroptosis mediated by activation of the NLRP3 inflammasome is a major contributor to neuronal death after ICH. However, the upstream mechanisms remain to be fully elucidated. Methods We performed integrative transcriptomic–proteomic profiling of mouse ICH brain tissues with in vivo functional validation. Annexin A2 (ANXA2), identified as a hub protein, was silenced via genetic knockdown. Neurological function, brain pathology, and pyroptotic signaling were assessed by behavioral tests, histology, Western blotting, immunofluorescence, and co-immunoprecipitation. Results Multi-omics and network analyses identified ANXA2 as a prominently upregulated hub protein after ICH. Co-immunoprecipitation demonstrated an association between ANXA2 and NLRP3, while ANXA2 silencing reduced NLRP3 inflammasome activation, decreased GSDMD cleavage and IL-1β/IL-18 secretion and significantly improved neurological function while alleviating brain injury. Conclusions This study reveals a previously unrecognized ANXA2–NLRP3–pyroptosis pathway in ICH, revealing a neuronal–immune convergence mechanism in inflammasome regulation. These findings provide new insight into neuronal pyroptosis after ICH and underscore ANXA2 as a predominantly neuronal factor associated with inflammasome activation in hemorrhagic stroke.
Wu et al. (2026) studied this question.