Zou Yingxin, Ruan Minghua, Feng Xu, Liu Fei, Liu Weihong, Chen Song, Chu Zhiyong
Naval Medical Center, Naval Medical University, Shanghai, China.
Mol Med. 2025 Apr 2;31(1):125. doi: 10.1186/s10020-025-01170-0.
Riboflavin kinase (RFK, also called flavokinase) is a catalytic enzyme that converts riboflavin to its active form in vivo. Dysfunction of the RFK gene has been associated with susceptibility to ischemic stroke. However, the protective role and mechanisms of RFK in ischemic stroke have not been elucidated.
Lentivirus-mediated RFK knock-up (RFK( +)) and knock-down (RFK(-)) were used to investigate the protective effect and mechanism of RFK in the rat middle cerebral artery occlusion (MCAO) model in vivo and in the oxygen and glucose deprivation (OGD) model of neurons in vitro; and the dependence of the protective effect of RFK on flavins was also investigated.
We demonstrated that RFK was an endogenous protein against ischemia brain injury both in vivo and in vitro experiments. RFK inhibited cerebral infarction, cerebral edema and neuronal apoptosis after cerebral ischemia. Its mechanisms include inhibition of the protein expression of Caspase 12 and Caspase 3 induced by cerebral ischemia, and thus inhibiting endoplasmic reticulum stress (ERS) and neuronal apoptosis; the protective effect of RFK depends on the presence of the flavoprotein Ero1; exogenous riboflavin supplementation protected cortical neurons from ischemic injury and prolonged the lifespan in stroke-prone spontaneously hypertensive rats with low RFK gene function, but this protective effect is limited and cannot completely reverse the decreasing trend of neuronal tolerance to ischemic injury caused by RFK gene dysfunction; the protective effect of RFK against ischemic injury is independent of the presence of flavins and their concentrations.
The present study demonstrates that RFK is an important regulatory molecule against ischemia brain injury and its mechanism involves inhibition of ERS. The protective effect of RFK is independent of the presence of flavins and their concentrations. RFK deserves further investigation as a promising target gene for the detection of stroke susceptibility. Flavins may be used as a preventive or adjunctive treatments for ischemic brain injury.
核黄素激酶（RFK，也称为黄素激酶）是一种催化酶，可在体内将核黄素转化为其活性形式。RFK基因功能障碍与缺血性中风易感性相关。然而，RFK在缺血性中风中的保护作用及其机制尚未阐明。
采用慢病毒介导的RFK基因上调（RFK(+)）和下调（RFK(-)），研究RFK在大鼠大脑中动脉闭塞（MCAO）体内模型和神经元氧糖剥夺（OGD）体外模型中的保护作用及机制；同时研究RFK保护作用对黄素的依赖性。
我们证明RFK在体内和体外实验中都是一种抗缺血性脑损伤的内源性蛋白。RFK可抑制脑缺血后的脑梗死、脑水肿和神经元凋亡。其机制包括抑制脑缺血诱导的Caspase 12和Caspase 3蛋白表达，从而抑制内质网应激（ERS）和神经元凋亡；RFK的保护作用依赖于黄素蛋白Ero1的存在；外源性补充核黄素可保护皮质神经元免受缺血性损伤，并延长RFK基因功能低下的易患中风自发性高血压大鼠的寿命，但这种保护作用有限，不能完全逆转由RFK基因功能障碍导致的神经元对缺血性损伤耐受性下降的趋势；RFK对缺血性损伤的保护作用与黄素的存在及其浓度无关。
本研究表明RFK是抗缺血性脑损伤的重要调节分子，其机制涉及抑制ERS。RFK的保护作用与黄素的存在及其浓度无关。RFK作为检测中风易感性的有前景的靶基因值得进一步研究。黄素可作为缺血性脑损伤的预防性或辅助性治疗药物。
