ACSF2-PGK1 interaction promotes ferroptosis in renal tubular epithelial cells of diabetic nephropathy by regulating Keap1/Nrf2 signaling.

IF 7.4 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Report Pub Date : 2025-12-01 Epub Date: 2025-07-16 DOI:10.1080/13510002.2025.2529618

Xinran Liu, Chaoyi Chen, Sai Zhu, Xiaomei Luo, Li Gao, Ziyun Hu, Yu Ma, Ling Jiang, Yonggui Wu

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引用次数: 0

Abstract

Objectives: Recent studies have highlighted the strong association between kidney disease and ferroptosis. However, the role of ferroptosis in diabetic nephropathy (DN) remains unclear. This study aimed to determine the role of ACSF2 in renal tubule injury in DN and its underlying mechanisms.

Methods: We established diabetic kidney disease models both in vivo, using db/db mice, and in vitro, using high glucose induced HK-2 cells.

Results: A significant upregulation of ACSF2 was observed in the renal tubules of patients with DN and db/db mice. ACSF2 expression correlated with renal tubule injury and renal function, indicating its potential as an independent biomarker in patients with DN. Silencing ACSF2 alleviated high glucose-induced renal tubular epithelial cell injury by reducing oxidative stress-induced ferroptosis in vivo and in vitro. Mechanistically, liquid chromatography-tandem mass spectrometry and co-immunoprecipitation demonstrated that ACSF2 specifically binds to PGK1. ACSF2 affected Keap1 dimerization by regulating PGK1 phosphorylation at serine 203, which subsequently affects the levels of NRF2. Moreover, PGK1 stabilizes ACSF2 via deubiquitination, establishing a positive feedback loop. The results provide evidence that the interaction between ACSF2 and PGK1 promotes DN progression by regulating oxidative stress-induced ferroptosis.

Discussion: ACSF2 participates in crosstalk between oxidative stress and ferroptosis. This could be a potential therapeutic target for DN.

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ACSF2-PGK1相互作用通过调节Keap1/Nrf2信号通路促进糖尿病肾病肾小管上皮细胞铁下垂。

目的：最近的研究强调了肾脏疾病和铁下垂之间的密切联系。然而，铁下垂在糖尿病肾病（DN）中的作用尚不清楚。本研究旨在确定ACSF2在DN肾小管损伤中的作用及其潜在机制。方法：在体内用db/db小鼠和体外用高糖诱导的HK-2细胞建立糖尿病肾病模型。结果：DN患者和db/db小鼠肾小管中ACSF2明显上调。ACSF2的表达与肾小管损伤和肾功能相关，表明其可能作为DN患者的独立生物标志物。在体内和体外实验中，沉默ACSF2可通过减少氧化应激诱导的铁上吊来减轻高糖诱导的肾小管上皮细胞损伤。在机制上，液相色谱-串联质谱和共免疫沉淀表明ACSF2特异性结合PGK1。ACSF2通过调节PGK1丝氨酸203的磷酸化影响Keap1二聚化，进而影响NRF2的水平。此外，PGK1通过去泛素化稳定ACSF2，建立正反馈回路。结果表明ACSF2和PGK1之间的相互作用通过调节氧化应激诱导的铁下垂来促进DN的进展。讨论：ACSF2参与氧化应激与铁下垂的串扰。这可能是DN的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Redox Report 生物-生化与分子生物学

CiteScore

6.10

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： Redox Report is a multidisciplinary peer-reviewed open access journal focusing on the role of free radicals, oxidative stress, activated oxygen, perioxidative and redox processes, primarily in the human environment and human pathology. Relevant papers on the animal and plant environment, biology and pathology will also be included. While emphasis is placed upon methodological and intellectual advances underpinned by new data, the journal offers scope for review, hypotheses, critiques and other forms of discussion.