FASEB J. 2026 Nov 15;40(21):e72414. doi: 10.1096/fj.202602543RR.
ABSTRACT
Early brain injury after subarachnoid hemorrhage (SAH) is chiefly marked by neuronal apoptosis and neuroinflammation, while the principal regulating molecules have yet to be identified. RBM47 exhibited considerable upregulation in the cerebral cortex of SAH mice and hemoglobin (Hb)-induced primary cortical neurons. Knockdown of RBM47 with intracerebroventricular injection of small interfering RNA improved neurobehavioral scores (modified Garcia score and beam balance test), mitigated brain edema and SAH grade, and decreased the quantity of FJC-positive and TUNEL-positive neurons in the cortex. Furthermore, RBM47 knockdown suppressed the expression of apoptotic proteins, obstructed HMGB1 nuclear to cytoplasmic translocation, and reduced TNF-α and IL-6 concentrations. In vitro results further validated that RBM47 knockdown diminished Hb-induced neuronal apoptosis and neuroinflammation. The transcription factor EGR1 directly bound to the RBM47 promoter and transcriptionally stimulated RBM47. RBM47 enhanced PARP1 expression by binding to the 3'UTR of PARP1 mRNA. Co-immunoprecipitation demonstrated a connection between PARP1 and HMGB1, facilitating HMGB1 release. We conducted label-free proteomics analysis on primary neurons following PARP1 knockdown and Hb therapy. Differentially expressed proteins were enriched in ADP ribosylation, regulation of necroptosis, and the extrinsic apoptotic pathway. GSEA revealed a large negative enrichment of the neuronal apoptotic process, while pathways associated with mitochondrial activity exhibited highly significant positive enrichment. EGR1 transcriptionally stimulates RBM47, which then enhances HMGB1 release by upregulating PARP1, therefore facilitating neuronal death and inflammation following SAH. PARP1 knockdown alters the mitochondrial protein expression profile and inhibits apoptosis and necroptosis. Targeting the EGR1/RBM47/PARP1/HMGB1 axis may provide an innovative therapeutic approach for SAH.
PMID:42963960 | DOI:10.1096/fj.202602543RR