Intracerebral hemorrhage (ICH) remains a devastating subtype of stroke with extremely high mortality and long-term neurological disability worldwide, and secondary neuronal apoptosis is the core pathological event driving poor functional prognosis in ICH patients. However, the precise molecular mechanisms governing post-ICH neuronal apoptosis still remain poorly defined, and effective targeted therapeutic strategies for ICH are still lacking clinically. Here we show that the p75 neurotrophin receptor (p75NTR) exacerbates ICH-induced neuronal injury by promoting the degradation of the deubiquitinase OTUB1. In a mouse model of ICH and hemin-treated HT22 hippocampal neurons, p75NTR and OTUB1 were significantly upregulated and co-localized in the cytoplasm. p75NTR directly interacted with OTUB1 through its intracellular domain (ICD). Functionally, p75NTR overexpression promoted K48-linked polyubiquitination and proteasomal degradation of OTUB1, leading to an increased Bax/Bcl-2 ratio and elevated cleaved caspase-3 levels. Rescue experiments validated that OTUB1 overexpression effectively reversed neuronal apoptosis triggered by p75NTR, whereas OTUB1 knockdown aggravated this apoptotic process. Collectively, our findings uncover a novel p75NTR-OTUB1 signaling cascade that modulates neuronal apoptosis following ICH. This work provides new mechanistic insight into post-ICH brain injury and offers a promising molecular target for developing intervention strategies against ICH-induced neuronal loss.
Cui et al. (Mon,) studied this question.