Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
Exp Cell Res. 2022 Nov 1;420(1):113340. doi: 10.1016/j.yexcr.2022.113340. Epub 2022 Sep 6.
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. HO treatment enhanced FOXO4 expression in HLEpiC cells. Short hairpin RNAs mediated FOXO4 silence aggravated HO-induced cell apoptosis. In addition, upon HO exposure, 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.
氧化应激损伤晶状体是大多数白内障的一个关键因素。叉头框 O4（FOXO4）是叉头框 O 家族的一个成员，在氧化应激中起着关键作用。FOXO4 在年龄相关性白内障患者的晶状体中上调，但它在白内障中的作用尚未阐明。在此，我们研究了 FOXO4 在晶状体上皮细胞氧化应激损伤中的作用和机制。HO 处理增强了 HLEpiC 细胞中 FOXO4 的表达。短发夹 RNA 介导的 FOXO4 沉默加剧了 HO 诱导的细胞凋亡。此外，在 HO 暴露下，沉默 FOXO4 降低了 SOD 和 CAT 活性，同时增加了细胞内 MDA 和 ROS 水平。FOXO4 沉默也抑制了 Nrf2 的核易位，随后降低了 Nrf2 调控的抗氧化基因 HO-1 和 NOQ-1 的表达。本研究还涉及 FOXO4 的外源性过表达，其表现出与 FOXO4 沉默相反的效果。从机制上讲，FOXO4 直接结合 TRIM25 的启动子并调节其转录，从而激活 Nrf2 信号。总之，在氧化应激条件下，FOXO4 的表达表现出代偿性上调，通过调节 TRIM25 的转录来发挥抗氧化作用，从而激活 Nrf2 信号。FOXO4/TRIM25/Nrf2 轴可能与白内障的病理机制有关。
