Dysregulation of the TNF-α-OTUD3-PPARγ signaling axis exacerbates retinal oxidative stress and inflammation in diabetic retinopathy

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-08-29 DOI:10.1016/j.lfs.2025.123933

Jialin Zhang , Zhen Wang , Junjun Liu , Wenchang Xu , Lu Lu , Na Zhou , Yongfeng Song

{"title":"Dysregulation of the TNF-α-OTUD3-PPARγ signaling axis exacerbates retinal oxidative stress and inflammation in diabetic retinopathy","authors":"Jialin Zhang , Zhen Wang , Junjun Liu , Wenchang Xu , Lu Lu , Na Zhou , Yongfeng Song","doi":"10.1016/j.lfs.2025.123933","DOIUrl":null,"url":null,"abstract":"<div><h3>Aims</h3><div>Diabetic retinopathy (DR) is one of the major complications of diabetes. In addition to hyperglycemia, various mechanisms contribute to the development of microvascular damage to the retina, which have not been fully elucidated. The aim of this study was to investigate Ovarian tumor domain-containing protein 3 (OTUD3)'s protection against DR by targeting peroxisome proliferator-activated receptor γ (PPARγ)-mediated dysfunction and identifying therapeutic strategies.</div></div><div><h3>Materials and methods</h3><div>We conducted clinical analysis of 208 type 2 diabetes mellitus (T2DM) patients with OTUD3 genotyping, combined with diabetic homozygous mutated (<em>Otud3</em><sup><em>−/−</em></sup>) mouse models and retinal pigment epithelium (RPE) cell lines (OTUD3 knockdown/mutation).</div></div><div><h3>Key findings</h3><div>We found increased hyperreflective foci (HRF) associated with an increased immune activation in diabetic <em>Otud3</em><sup><em>−/−</em></sup> mice compared to <em>Otud3</em> wild-type (<em>Otud3</em><sup><em>+/+</em></sup>) mice. OTUD3 knockdown or mutated cells showed increased cell dysfunction and oxidative stress markers under inflammatory conditions. Further upstream transcription factors predict analysis suggest PPARγ as the potential target of OTUD3. Finally, we found PPARγ agonist could rescue the phenotype in RPE cells characterized by increased ROS levels, enhanced migration, and elevated apoptosis resulting from OTUD3 loss of function through knockdown or mutation.</div></div><div><h3>Significance</h3><div>Our study offers novel insights into how deubiquitylase OTUD3 maintains the normal function of the retina by deubiquitylating PPARγ and provides a novel therapeutic target for this vision-threatening diabetic complications.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"380 ","pages":"Article 123933"},"PeriodicalIF":5.1000,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0024320525005685","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Aims

Diabetic retinopathy (DR) is one of the major complications of diabetes. In addition to hyperglycemia, various mechanisms contribute to the development of microvascular damage to the retina, which have not been fully elucidated. The aim of this study was to investigate Ovarian tumor domain-containing protein 3 (OTUD3)'s protection against DR by targeting peroxisome proliferator-activated receptor γ (PPARγ)-mediated dysfunction and identifying therapeutic strategies.

Materials and methods

We conducted clinical analysis of 208 type 2 diabetes mellitus (T2DM) patients with OTUD3 genotyping, combined with diabetic homozygous mutated (Otud3^−/−) mouse models and retinal pigment epithelium (RPE) cell lines (OTUD3 knockdown/mutation).

Key findings

We found increased hyperreflective foci (HRF) associated with an increased immune activation in diabetic Otud3^−/− mice compared to Otud3 wild-type (Otud3^+/+) mice. OTUD3 knockdown or mutated cells showed increased cell dysfunction and oxidative stress markers under inflammatory conditions. Further upstream transcription factors predict analysis suggest PPARγ as the potential target of OTUD3. Finally, we found PPARγ agonist could rescue the phenotype in RPE cells characterized by increased ROS levels, enhanced migration, and elevated apoptosis resulting from OTUD3 loss of function through knockdown or mutation.

Significance

Our study offers novel insights into how deubiquitylase OTUD3 maintains the normal function of the retina by deubiquitylating PPARγ and provides a novel therapeutic target for this vision-threatening diabetic complications.

查看原文本刊更多论文

TNF-α-OTUD3-PPARγ信号轴的失调加剧了糖尿病视网膜病变的视网膜氧化应激和炎症

目的糖尿病视网膜病变（DR）是糖尿病的主要并发症之一。除高血糖外，视网膜微血管损伤的发生机制多种多样，目前尚未完全阐明。本研究旨在探讨卵巢肿瘤结构域蛋白3 （OTUD3）通过靶向过氧化物酶体增殖物激活受体γ (PPARγ)介导的功能障碍，并确定治疗策略，对DR的保护作用。材料与方法结合糖尿病纯合突变（OTUD3 - / -）小鼠模型和视网膜色素上皮（RPE）细胞系（OTUD3敲低/突变），对208例OTUD3基因分型的2型糖尿病（T2DM）患者进行临床分析。我们发现，与Otud3野生型（Otud3+/+）小鼠相比，糖尿病Otud3 - / -小鼠的高反射灶（HRF）增加与免疫激活增加有关。在炎症条件下，OTUD3敲低或突变的细胞显示出细胞功能障碍和氧化应激标志物的增加。进一步的上游转录因子预测分析表明PPARγ是OTUD3的潜在靶标。最后，我们发现PPARγ激动剂可以挽救因OTUD3敲低或突变导致功能丧失而导致ROS水平升高、迁移增强和凋亡升高的RPE细胞的表型。我们的研究为去泛素化酶OTUD3如何通过去泛素化PPARγ来维持视网膜的正常功能提供了新的见解，并为这种威胁视力的糖尿病并发症提供了新的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.