FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling.
FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling.
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DOI：
10.1016/j.yexcr.2022.113340
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发表时间：
2022-09
影响因子：
3.7
通讯作者：
Xin Yang;Fengyan Zhang;Xuhui Liu;J. Meng;Shanshan Du;J. Shao;Jingjing Liu;Mengyuan Fang
中科院分区：
文献类型：
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作者：
Xin Yang;Fengyan Zhang;Xuhui Liu;J. Meng;Shanshan Du;J. Shao;Jingjing Liu;Mengyuan Fang
对透镜的氧化应激损伤是大多数白内障的关键因素。FOXO 4是叉头盒O家族的成员之一，在氧化应激中起着关键作用。FOXO 4在年龄相关性白内障患者的透镜中上调，但其在白内障中的作用尚未阐明。在此，我们研究FOXO 4在透镜上皮细胞氧化应激损伤中的作用和机制。H_2O_2处理可增强HLEpiC细胞FOXO_4的表达。短发夹RNA介导的FOXO 4沉默加重了H2 O2诱导的细胞凋亡。此外，H2 O2暴露后，FOXO 4的沉默降低了SOD和CAT活性，并增加了细胞内MDA和ROS水平。FOXO 4沉默也抑制Nrf 2核转位，随后降低Nrf 2控制的抗氧化基因HO-1和NOQ-1的表达。FOXO 4的外源性过表达也参与了这项研究，并表现出FOXO 4沉默的相反效果。在机制上，FOXO 4直接结合TRIM 25的启动子并调节其转录，从而激活Nrf 2信号传导。综上所述，在氧化应激条件下，FOXO 4的表达表现出补偿性上调，并通过调节TRIM 25的转录，从而激活Nrf 2信号传导，表现出抗氧化作用。FOXO 4/TRIM 25/Nrf 2轴可能与白内障的发病机制有关。
Oxidative stress damage to the lens is a key factor in most cataracts. Forkhead box O 4 (FOXO4), a member of the forkhead box O family, plays a pivotal role in oxidative stress. FOXO4 is upregulated in lens of age-related cataract patients, but its role in cataract has not been elucidated. Herein, we investigated the role and mechanism of FOXO4 during oxidative stress damage in lens epithelial cells. H2O2treatment enhanced FOXO4 expression in HLEpiC cells. Short hairpin RNAs mediated FOXO4 silence aggravated H2O2-induced cell apoptosis. In addition, upon H2O2exposure, silencing of FOXO4 reduced SOD and CAT activities, as well as increased intracellular MDA and ROS levels. FOXO4 silencing also inhibited Nrf2 nuclear translocation, followed by reducing the expressions of Nrf2-governed antioxidant genes HO-1 and NOQ-1. Exogenous overexpression of FOXO4 was also involved in this study and exhibited opposite effects of FOXO4-silencing. Mechanistically, FOXO4 directly bound the promoter of TRIM25 and regulated its transcription, thereby activating the Nrf2 signaling. Taken together, in the condition of oxidative stress, the expression of FOXO4 showed a compensatory upregulation and it exhibited an anti-oxidative effect by modulating the transcription of TRIM25, thus activating the Nrf2 signaling. The FOXO4/TRIM25/Nrf2 axis may be associated with the pathological mechanisms of cataract.