FoxO1 promotes high glucose-induced inflammation and cataract formation via JAK1/STAT1.

IF 2.4 3区医学 Q2 OPHTHALMOLOGY Graefe’s Archive for Clinical and Experimental Ophthalmology Pub Date : 2025-06-01 Epub Date: 2025-01-29 DOI:10.1007/s00417-025-06744-6

Yike Li, An-Peng Pan, Yishan Ye, Xu Shao, Ruixue Tu, Yang Liu, A-Yong Yu

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Abstract

Purpose: To investigate whether in diabetic cataract (DC), FoxO1 regulates high glucose (HG)-induced activation of NLRC4/IL-6 inflammatory mediators in human lens epithelial cells (SRA01/04) via the JAK1/STAT1 pathway, leading to cataract formation.

Methods: Expression levels of FoxO1, inflammatory factor IL-6 and inflammatory vesicle NLRC4 were examined in SRA01/04 under high glucose (HG) stress at 25-150 mM. Rat lenses were also cultured using HG medium with or without the addition of the FoxO1 inhibitor AS1842856 and the JAK1 agonist RO8191. 5.5 mM glucose concentration group (NG) was used as a control. Real-time PCR, Western blots, and immunofluorescent staining evaluated the mRNA and protein levels of FoxO1, NLRC4, and IL-6. Apoptosis, cell viability, and EDU Staining were also assessed.

Results: HG stimulation induced elevated FoxO1 expression and caused NLRC4/IL-6 activation in a concentration-dependent manner. Whereas knockdown of FoxO1 inhibited the high expression of NLRC4/IL-6 inflammatory mediators in response to HG stimulation. The growth of SRA01/04 was inhibited under HG condition, and the cell proliferation ability was restored and even promoted by knocking out FoxO1. HG incubation of rat lens resulted in lens clouding and cataract formation, which was prevented by AS1842856 treatment and reversed by RO8191.

Conclusion: FoxO1 positively regulates HG-induced SRA01/04 inflammatory activation through the JAK1/STAT1 pathway and promotes DC. This provides a feasible strategy for the treatment of diabetic cataract.

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fox01通过JAK1/STAT1促进高糖诱导的炎症和白内障形成。

目的：探讨FoxO1是否在糖尿病性白内障（DC）中通过JAK1/STAT1通路调控高糖（HG）诱导的人晶状体上皮细胞（SRA01/04） NLRC4/IL-6炎症介质激活，导致白内障形成。方法：在高糖（HG）应激25-150 mM时，检测SRA01/04中FoxO1、炎症因子IL-6和炎性囊泡NLRC4的表达水平。在HG培养基中分别添加或不添加FoxO1抑制剂AS1842856和JAK1激动剂RO8191培养大鼠晶体。以5.5 mM葡萄糖浓度组（NG）为对照。Real-time PCR、Western blots和免疫荧光染色评估FoxO1、NLRC4和IL-6的mRNA和蛋白水平。细胞凋亡、细胞活力和EDU染色也进行了评估。结果：HG刺激诱导FoxO1表达升高，NLRC4/IL-6激活呈浓度依赖性。而FoxO1的敲低抑制NLRC4/IL-6炎症介质在HG刺激下的高表达。HG条件下，SRA01/04的生长受到抑制，敲除fox01后，细胞增殖能力得以恢复甚至促进。HG对大鼠晶状体的孵育导致晶状体混浊和白内障的形成，AS1842856可以预防这种情况，RO8191可以逆转。结论：FoxO1通过JAK1/STAT1通路正向调节hg诱导的SRA01/04炎症激活，促进DC的发生。为糖尿病性白内障的治疗提供了一种可行的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Graefe’s Archive for Clinical and Experimental Ophthalmology 医学-眼科学

CiteScore

5.40

自引率

7.40%

发文量

398

审稿时长

3 months

期刊介绍： Graefe''s Archive for Clinical and Experimental Ophthalmology is a distinguished international journal that presents original clinical reports and clini-cally relevant experimental studies. Founded in 1854 by Albrecht von Graefe to serve as a source of useful clinical information and a stimulus for discussion, the journal has published articles by leading ophthalmologists and vision research scientists for more than a century. With peer review by an international Editorial Board and prompt English-language publication, Graefe''s Archive provides rapid dissemination of clinical and clinically related experimental information.