目的 探讨F-box/富含亮氨酸重复蛋白4（FBXL4）通过调控动力蛋白相关蛋白1（Drp1）介导的线粒体动力学抑制氧化应激和凋亡，保护心脏骤停（CA）后心肺复苏（CPR）致脑缺血再灌注损伤（CIRI）的分子机制。 方法 选取48只雄性SD大鼠随机分为4组（每组6只）：Control组、Control + 过表达FBXL4（OE-FBXL4）组、CA/CPR组、CA/CPR + OE-FBXL4组，另设生存分析，每组6只。自主循环恢复（ROSC）后24 h处死取材，检测神经功能缺损评分（NDS）、7 d生存率；采用RT-qPCR和Western blot检测FBXL4、Drp1 mRNA及蛋白表达；Western blot检测线粒体动力学蛋白；免疫共沉淀验证FBXL4与Drp1相互作用；HE染色和尼氏（Nissl）染色观察脑组织病理；透射电镜观察线粒体超微结构；生化法检测丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽（GSH）、过氧化氢酶（CAT）评估氧化应激水平；Western blot检测凋亡相关蛋白B细胞淋巴瘤-2相关X蛋白（Bax）、B细胞淋巴瘤-2（Bcl-2）、半胱氨酸天冬氨酸蛋白酶-3/8（Caspase-3/8）表达。 结果 （1）与Control组相比，CA/CPR组大鼠NDS评分显著降低（P < 0.01），7 d生存率下降；脑组织FBXL4mRNA及蛋白表达显著下调（均P < 0.01），Drp1、Fis1、MFF表达显著上调（均P < 0.01），OPA1、MFN1、MFN2表达显著下调（均P < 0.01）；HE和Nissl染色显示皮层及海马CA1、CA3区神经元排列紊乱、胞体萎缩、尼氏小体溶解，存活神经元数量减少；TEM显示线粒体肿胀、空泡化、嵴断裂，呈碎片化；MDA含量升高（P < 0.01），SOD、GSH、CAT活性降低（均P < 0.01）；Bax/Bcl-2比值升高（P < 0.01），Caspase-3、Caspase-8表达增加（均P < 0.01）。（2）与CA/CPR组相比，CA/CPR + OE-FBXL4组NDS评分显著提高（P < 0.01），7 d生存率明显上升；FBXL4蛋白维持高水平表达；Drp1、Fis1、MFF蛋白水平下降（均P < 0.01），OPA1、MFN1、MFN2蛋白水平上升（均P < 0.01）；HE和Nissl染色显示神经元形态改善，变性坏死细胞减少，存活神经元数量增加；TEM显示线粒体恢复管网状结构，嵴结构清晰完整；MDA含量降低（P < 0.01），SOD、GSH、CAT活性升高（均P < 0.01）；Bax/Bcl-2比值下降（P < 0.01），Caspase-3、Caspase-8表达减少（均P < 0.01）。（3）Co-IP实验证实FBXL4与Drp1存在蛋白-蛋白相互作用；Control + OE-FBXL4组FBXL4-Drp1复合物形成量较Control组显著增加（P < 0.01），CA/CPR组复合物形成减少，CA/CPR + OE-FBXL4组结合量显著恢复。 结论 FBXL4是CA/CPR后脑损伤的关键保护性调控因子，其过表达可通过靶向Drp1恢复线粒体动力学平衡，进而抑制氧化应激和神经元凋亡；同时，Nrf2/HO-1通路的进一步上调可能协同参与了FBXL4的抗氧化保护作用。

Objective To explore the molecular mechanism by which F-box/leucine-rich repeat protein 4 （FBXL4） inhibits oxidative stress and apoptosis， and prevents cerebral ischemia-reperfusion injury （CIRI） induced by cardiopulmonary resuscitation （CPR） after cardiac arrest （CA） through regulating dynamin-related protein 1 （Drp1）-mediated mitochondrial dynamics. Methods A total of 48 male SD rats were randomly divided into 4 groups， with 6 rats in each group （n = 6）： Control group， Control + FBXL4 overexpression （OE-FBXL4） group， CA/CPR group， and CA/CPR + OE-FBXL4 group. Survival analysis was also conducted， with 6 cases in each group. The rats were sacrificed at 24 h after the return of spontaneous circulation （ROSC） for sampling. The neurological deficit score （NDS） and the 7-day survival rate were detected. The expressions of FBXL4 and Drp1 mRNA and proteins were determined by RT-qPCR and Western blot. The expressions of mitochondrial dynamics proteins were measured by Western blot. The interaction between FBXL4 and Drp1 was verified by the co-immunoprecipitation method. The pathology of brain tissues was examined by HE staining and Nissl staining. The ultrastructure of mitochondria was observed using a transmission electron microscope. The levels of malondialdehyde （MDA）， superoxide dismutase （SOD）， glutathione （GSH）， and catalase （CAT） were measured by a biochemical method to evaluate the oxidative stress level. The expressions of apoptosis-related proteins ［B cell lymphoma-2 associated X protein （Bax）， B cell lymphoma-2 （Bcl-2）， cysteine aspartase peptidases （Caspase）-3/8］ were measured by Western blot. Results （1） When compared to the Control group， the Neurological Deficit Score （NDS） in the CA/CPR group was significantly lower （P < 0.01）， and the 7-day survival rate was also reduced. In the brain tissues， the expressions of FBXL4 mRNA and protein were significantly down-regulated （all P < 0.01）， while the expressions of Drp1， Fis1， and MFF were significantly up-regulated （all P < 0.01）， and the expressions of OPA1， MFN1， and MFN2 were significantly down-regulated （all P < 0.01）. HE and Nissl staining results indicated that in the cortex and the CA1 and CA3 regions of the hippocampus， neurons were arranged in a disordered manner， with cell body atrophy， dissolution of Nissl bodies， and a decreased number of surviving neurons. Transmission electron microscopy （TEM） revealed mitochondrial swelling， vacuolization， cristae fracture， and fragmentation. The content of MDA was increased （P < 0.01）， whereas the activities of SOD， GSH， and CAT were decreased （all P < 0.01）. The Bax/Bcl-2 ratio was elevated （P < 0.01）， and the expressions of Caspase-3 and Caspase-8 were increased （both P < 0.01）. （2） In comparison with the CA/CPR group， the Neurological Deficit Score （NDS） was significantly elevated in the CA/CPR + OE-FBXL4 group （P < 0.01）， and the 7-day survival rate was also significantly increased. The expression of the FBXL4 protein was at a high level. The levels of Drp1， Fis1， and MFF proteins decreased （all P < 0.01）， while the levels of OPA1， MFN1， and MFN2 proteins increased （all P < 0.01）. HE and Nissl staining indicated an improvement in neuronal morphology， a reduction in the number of degenerated and necrotic cells， and an increase in the number of survived neurons. Transmission electron microscopy （TEM） revealed the recovery of the mitochondrial pipe-network structure and a clear and complete cristae structure. The content of MDA decreased （P < 0.01）， and the activities of SOD， GSH， and catalase （CAT） increased （all P < 0.01）. The Bax/Bcl-2 ratio decreased （P < 0.01）， and the expressions of Caspase-3 and Caspase-8 decreased （both P < 0.01）. （3） A Co-IP experiment confirmed a protein-protein interaction between FBXL4 and Drp1. The formation amount of the FBXL4-Drp1 complex in the Control + OE-FBXL4 group was significantly higher than that in the Control group （P < 0.01）. The formation amount of the FBXL4-Drp1 complex decreased in the CA/CPR group， and the binding amount was significantly restored in the CA/CPR + OE-FBXL4 group. Conclusions FBXL4 serves as a crucial protective regulator against brain injury following CA/CPR. The overexpression of FBXL4 can restore mitochondrial dynamic balance by targeting Drp1， thus suppressing oxidative stress and neuronal apoptosis. Moreover， the further up-regulation of the Nrf2/HO-1 pathways may be synergistically involved in the antioxidant protection provided by FBXL4.