Bourourou Miled, Melis Nicolas, Cougnon Marc, Laffet Gilbert, Duranton Christophe, Rubera Isabelle, Maurin Thomas, Heurteaux Catherine, Hauet Thierry, Duca Maria, Pisani Didier F, Blondeau Nicolas, Tauc Michel
Université Côte d'Azur, CNRS UMR7275, INSERM U1323, IPMC, Sophia Antipolis, France.
Université de Poitiers, INSERM, IRMETIST, CHU de Poitiers, La Milétrie, Poitiers, France.
J Cereb Blood Flow Metab. 2025 Jun 19:271678X251347810. doi: 10.1177/0271678X251347810.
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 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 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.
中风给全球带来了巨大的社会经济负担，但缺乏临床批准的抗缺血药物以及溶栓治疗的可及性有限，凸显了对新型治疗靶点的迫切需求。为了确定新型抗缺血治疗靶点，我们对高度缺氧敏感的上皮细胞进行体外缺血/再灌注，并在有和没有真核起始因子5A（eIF5A）抑制的情况下进行了全面的蛋白质组学分析，这一策略最近因其在减轻缺血缺氧损伤方面的功效而得到认可。通过几个关键发现，我们确定了丝氨酰 - tRNA合成酶（serRS）作为一个有前景的靶点。首先，我们验证了在缺血/再灌注模型中抑制serRS能高效减少细胞死亡。随后，我们证明在短暂性局灶性脑缺血小鼠模型中，抑制serRS可显著减少梗死体积，并减轻运动和认知缺陷，突出了靶向serRS的治疗潜力。总体而言，这项概念验证研究揭示serRS是一种新型抗缺血靶点，为发现和开发具有治疗缺血相关疾病前景的新抑制剂奠定了基础。
