Cha Jun Seok, Kim Jinyoung, Cho Junyoung, Lee Jungho, Kim Jiyoon, Chae Dongwoo
Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
iScience. 2025 Aug 7;28(9):113270. doi: 10.1016/j.isci.2025.113270. eCollection 2025 Sep 19.
Beclin-1 plays a pivotal role in the interplay between autophagy and apoptosis in ischemic stroke, influencing both cell survival and death. We developed a mathematical model incorporating the dual role of Beclin-1 to simulate Beclin-1-induced autophagy and apoptosis under varying ischemic stress conditions. The model predicts a critical threshold of Beclin-1 expression, beyond which apoptosis is triggered, with this threshold decreasing as stress severity increases. To validate the model predictions, we conducted Beclin-1 overexpression and knockdown experiments under mild and severe oxygen-glucose deprivation (OGD) conditions and Beclin-1 knockdown in a photothrombotic mice model. The experiments demonstrated that Beclin-1 overexpression increases Caspase activation under severe OGD, while knockdown reduces it; the opposite effects were observed under mild OGD. Simulations suggest that modulating Beclin-1 expression could extend the therapeutic window for thrombolysis. Our approach provides insights into the dual roles of Beclin-1 and highlights potential strategies for neuroprotection.
Beclin-1在缺血性中风的自噬与凋亡相互作用中起关键作用，影响细胞的存活与死亡。我们构建了一个纳入Beclin-1双重作用的数学模型，以模拟在不同缺血应激条件下Beclin-1诱导的自噬和凋亡。该模型预测了Beclin-1表达的临界阈值，超过此阈值会触发凋亡，且随着应激严重程度增加该阈值降低。为验证模型预测，我们在轻度和重度氧糖剥夺（OGD）条件下进行了Beclin-1过表达和敲低实验，并在光血栓形成小鼠模型中进行了Beclin-1敲低实验。实验表明，Beclin-1过表达在重度OGD下会增加半胱天冬酶激活，而敲低则会降低；在轻度OGD下观察到相反的效果。模拟结果表明，调节Beclin-1表达可延长溶栓治疗窗口。我们的方法为Beclin-1的双重作用提供了见解，并突出了神经保护的潜在策略。
