Post-stroke depression (PSD) is one of the most familiar complications of stroke, which refers to stroke patients who have varying degrees of depression (lasts for >2 weeks). SET domain-containing 3 (SETD3) is a conserved histone H3 methyltransferase, and the role of SETD3 in some diseases is increasingly being explored. However, the effects of SETD3 in PSD remain unclear. In this study, the PSD rat model was firstly constructed by Endothelin-1 injection combined with chronic unpredictable mild stress, and we discovered that SETD3 expression was up-regulated in PSD rat model. Additionally, SETD3 knockdown relieved the depressive symptom of PSD. Moreover, SETD3 knockdown promoted proliferation and differentiation of neural stem cells (NSCs). Due to the critical role of vascular endothelial growth factor (VEGF) in antidepressant and SETD3 can negatively regulate VEGF, we speculated that SETD3 may regulate PSD progression through VEGF. Our results demonstrated that SETD3 knockdown up-regulated VEGF expression. Furthermore, SETD3 modulated the proliferation and differentiation of NSCs through regulating VEGF expression. In conclusion, our study indicated that up-regulation of SETD3 contributed to PSD progression in rats through negatively regulating VEGF expression. The findings of this work suggest that SETD3 may be a promising target for treating PSD in the future.

卒中后抑郁（PSD）是卒中最常见的并发症之一，是指有不同程度抑郁（持续>2周）的卒中患者。含SET结构域3（SETD3）是一种保守的组蛋白H3甲基转移酶，SETD3在某些疾病中的作用正在被越来越多地探索。然而，SETD3 在 PSD 中的作用仍不清楚。本研究首次采用Endothelin-1注射联合慢性不可预知的轻度应激构建了PSD大鼠模型，发现在PSD大鼠模型中SETD3表达上调。此外，SETD3 敲低缓解了 PSD 的抑郁症状。此外，SETD3 敲低促进了神经干细胞 (NSCs) 的增殖和分化。由于血管内皮生长因子 (VEGF) 在抗抑郁药中的关键作用，而 SETD3 可以负调节 VEGF，我们推测 SETD3 可能通过 VEGF 调节 PSD 进展。我们的结果表明，SETD3 敲低上调了 VEGF 表达。此外，SETD3通过调节VEGF表达来调节NSCs的增殖和分化。总之，我们的研究表明，SETD3 的上调通过负调节 VEGF 表达促进了大鼠的 PSD 进展。这项工作的结果表明，SETD3 可能是未来治疗 PSD 的有希望的靶点。SETD3通过调节VEGF表达来调节NSCs的增殖和分化。总之，我们的研究表明，SETD3 的上调通过负调节 VEGF 表达促进了大鼠的 PSD 进展。这项工作的结果表明，SETD3 可能是未来治疗 PSD 的有希望的靶点。SETD3通过调节VEGF表达来调节NSCs的增殖和分化。总之，我们的研究表明，SETD3 的上调通过负调节 VEGF 表达促进了大鼠的 PSD 进展。这项工作的结果表明，SETD3 可能是未来治疗 PSD 的有希望的靶点。