Targeting seryl-tRNA synthetase to unlock ischemic resilience in stroke – Insights from a proof-of-concept study

Stroke imposes significant global socio-economic burdens, yet the absence of clinically approved anti-ischemic drugs and limited thrombolysis availability underscore the critical need for novel therapeutic target. To identify novel anti-ischemic therapeutic targets, we conducted a comprehensive proteomics analysis subsequent to in vitro ischemia/reperfusion of epithelial cells highly sensitive to oxygen deprivation with and without eIF5A inhibition, a strategy recently acknowledged for its efficacy in alleviating ischemic-anoxic damage. We identified seryl-tRNA synthetase (serRS) as a promising target through several key findings. Initially, we validated its inhibition as highly efficient in reducing cell death in an <i>in vitro</i> model of ischemia/reperfusion. Subsequently, we demonstrated that inhibition of serRS substantially decreased infarct volume and alleviated both motor and cognitive deficits in a murine model of transient focal cerebral ischemia, underscoring the <i>in vivo</i> therapeutic potential of targeting serRS. Overall, this Proof-of-Concept study unveils serRS as a novel anti-ischemic target, laying groundwork for the discovery and development of new inhibitors with therapeutic promise against ischemic-related diseases.