<scp>HDAC</scp> Inhibitor <scp>SAHA</scp> Attenuates Inflammatory Injury in Subarachnoid Hemorrhage by Suppressing <scp>NLRP1</scp> Signaling‐Mediated Neuronal Ferroptosis via Enhanced <scp>KLF2</scp> Acetylation

Subarachnoid hemorrhage (SAH) is an emergency with high mortality and disability rates. Targeting ferroptosis shows potential for ameliorating neuroinflammatory injury after SAH. A rat model of SAH was established via the endovascular puncture method. Suberoylanilide hydroxamic acid (SAHA) was intraperitoneally injected into rats. Neurological function and cerebral edema were evaluated. Primary neuronal cells were treated with oxyhemoglobin as a cellular in vitro model of SAH. Inflammatory cytokines were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Ferroptosis was evaluated by assessing malondialdehyde, glutathione, iron, and lipid reactive oxygen species. The acetylation and ubiquitination of krüppel-like factor 2 (KLF2) were determined by immunoprecipitation and Western blotting. The binding of KLF2 to nod-like receptor family pyrin domain-containing 1 (NLRP1) promoter was assessed by luciferase and chromatin immunoprecipitation assays. SAHA demonstrated significant protective effects on SAH by ameliorating ferroptosis and neuroinflammatory injury in SAH models. Mechanistically, SAHA upregulated KLF2 protein expression by promoting its acetylation. This enhanced acetylation concurrently inhibited neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4)-mediated ubiquitination and subsequent degradation of KLF2 protein. Further investigation revealed that KLF2 directly suppressed NLRP1 expression via binding to the NLRP1 promoter in neuronal cells. KLF2 knockdown activated NLRP1 signaling and attenuated SAHA's beneficial effects on ferroptosis and inflammatory injury after SAH. Taken together, SAHA enhances KLF2 acetylation to block NEDD4-mediated ubiquitination and degradation, thereby upregulating KLF2 expression. The increased KLF2 subsequently binds to the NLRP1 promoter to repress its transcriptional activation, ultimately inhibiting NLRP1 signaling-driven neuronal ferroptosis and ameliorating neuroinflammatory injury in SAH.