ZFP36 attenuates neuronal apoptosis and pyroptosis through inhibiting TXNIP/NLRP3 pathway in hypoxic-ischemic brain damage.

Hypoxic-ischemic brain damage (HIBD) is a major cause of neonatal mortality and long-term neurological impairment. Neuroinflammation plays a critical role in neuronal injury following HIBD. Zinc finger protein 36 (ZFP36), an RNA-binding protein that targets adenine-uridine-rich elements (AREs), exhibits anti-inflammatory properties, yet its role in HIBD remains unclear. In this study, we observed significant upregulation of ZFP36 expression in the hippocampal neurons of neonatal rats with HIBD and in HT22 hippocampal neuronal cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Knockdown of ZFP36 via adeno-associated virus (AAV) in neonatal rats exacerbated HIBD-induced hippocampal neuronal injury, cerebral infarction, and neurological deficits, whereas ZFP36 overexpression via AAV markedly ameliorated these outcomes. Similarly, ZFP36 knockdown in HT22 cells using lentivirus aggravated OGD/R-induced neuronal apoptosis and pyroptosis, while ZFP36 overexpression conferred protection. Mechanistically, ZFP36 can directly binds to the ARE within the 3'-untranslated region (3'-UTR) of thioredoxin-interacting protein (TXNIP), a key activator of the NOD-like receptor protein 3 (NLRP3) inflammasome, promoting TXNIP mRNA destabilization and degradation. This reduction in TXNIP impairs the TXNIP-NLRP3 interaction, thereby inhibiting NLRP3 inflammasome activation and neuroinflammation in HIBD. Collectively, our findings suggest that ZFP36 protects against HIBD through suppressing the TXNIP/NLRP3 inflammasome pathway and highlight ZFP36 as a potential therapeutic target for HIBD.