Abstract
BACKGROUND: Ischemic stroke is a leading cause of morbidity and mortality worldwide, yet available therapeutic strategies remain limited. La ribonucleoprotein domain family member 7 (LARP7), a critical regulator of RNA stability and transcriptional control, participates in cellular stress responses and inflammatory modulation. Emerging evidence suggests LARP7's involvement in neuroinflammation and neuronal survival, yet its role in ischemic stroke pathogenesis is still poorly understood. METHODS: We systematically investigated LARP7 expression in patients with acute ischemic stroke (AIS), mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R), and neurons exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). To elucidate the role of LARP7 in ischemic stroke, we generated neuron-specific LARP7 knockout mice, and employed a lentiviral delivery system for neuronal LARP7 overexpression. Protein interactions between LARP7-Sirt1 and Sirt1-NLRP3 were assessed using co-immunoprecipitation, proximity ligation assay, domain deletion analysis, and acetyl-proteomics. Furthermore, a potential LARP7 activator was identified through virtual screening, and its activation efficacy and neuroprotective effects were evaluated. RESULTS: LARP7 was markedly downregulated in the ischemic brain tissues from AIS patients and MCAO/R mice, as well as in OGD/R neurons. Neuronal LARP7 deficiency exacerbated neuronal pyroptosis and neurological deficits following ischemic stroke, which could be partially rescued by pharmacological activation of Sirt1. Mechanistically, LARP7's C-terminal domain interacted with the N-terminal domain of Sirt1 to enhance Sirt1 deacetylase activity, which facilitated NLRP3 deacetylation at K21/K22/K24, thereby inhibiting inflammasome assembly and subsequent neuronal pyroptosis. Furthermore, sorafenib tosylate was identified as a potential LARP7 activator with demonstrated neuroprotective effects. CONCLUSION: LARP7 enhances Sirt1 deacetylase activity to regulate NLRP3 deacetylation, thereby inhibiting inflammasome assembly and neuronal pyroptosis after ischemic stroke. Targeting LARP7 could represent a promising therapeutic strategy for ischemic stroke.