Inhibition of Lactate Accumulation via USP38-Mediated MCT1 Deubiquitination Activates AKT/mTOR Signaling to Mitigate PM2.5-Induced Lung Injury

IF 2.6 4区医学 Q2 MEDICAL LABORATORY TECHNOLOGY

Journal of Clinical Laboratory Analysis Pub Date : 2025-04-06 DOI:10.1002/jcla.70028

Zixiao Chen, Jing Cao, Shujie Hou, Lingshan Chao, Jingwen Li, Zaixing Jia, Siqin Han, Jialun Chen, Xixin Yan

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Abstract

Background

Lactate, traditionally viewed as a glycolysis byproduct, has emerged as an important mediator influencing immunity, inflammation, and tissue damage. While PM2.5 exposure is known to cause various metabolic disturbances, the role of lactate metabolism in PM2.5-induced lung injury remains unclear. This study aims to elucidate the mechanisms underlying PM2.5-induced lung injury from a metabolic perspective.

Methods

Lactate and pyruvate assays were performed to assess metabolic changes following PM2.5 exposure. Protein expression and tissue damage were assessed using Western blot, IHC, ELISA, and TUNEL staining. The biological role of USP38 in PM2.5-induced injury was identified using gain- and loss-of-function experiments. Co-immunoprecipitation and ubiquitination assays were conducted to analyze the interaction between USP38 and MCT1, as well as the regulation of MCT1 deubiquitination. The role of MCT1 in lactate metabolism and PM2.5-induced apoptosis was validated through gene editing. Proteomics revealed the potential mechanisms involved in USP38 regulation of apoptosis.

Results

Our results demonstrated that PM2.5 exposure induced lactate accumulation, leading to cell apoptosis and lung injury. USP38 stabilized MCT1 expression by deubiquitination, facilitating lactate export and reducing apoptosis and lung injury caused by lactate accumulation. Mechanistically, PM2.5 increased lactate production, suppressed AKT/mTOR pathway activation, and promoted apoptosis and lung injury. USP38 promoted lactate export through MCT1, activated the AKT/mTOR pathway, and mitigated PM2.5-induced lung injury.

Conclusion

USP38 reduces lactate accumulation by promoting AKT/mTOR pathway activation through MCT1-mediated lactate export, thereby alleviating PM2.5-induced lung injury. These findings reveal a novel mechanism of PM2.5-related lung injury and highlight potential therapeutic targets.

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通过usp38介导的MCT1去泛素化抑制乳酸积累激活AKT/mTOR信号减轻pm2.5诱导的肺损伤

背景：乳酸盐传统上被视为糖酵解的副产物，现已成为影响免疫、炎症和组织损伤的重要介质。虽然已知 PM2.5 暴露会导致各种代谢紊乱，但乳酸代谢在 PM2.5 诱导的肺损伤中的作用仍不清楚。本研究旨在从代谢角度阐明PM2.5诱发肺损伤的机制：方法：进行乳酸和丙酮酸测定，以评估 PM2.5 暴露后的代谢变化。使用 Western 印迹、IHC、ELISA 和 TUNEL 染色评估蛋白质表达和组织损伤。通过功能增益和功能缺失实验确定了 USP38 在 PM2.5 诱导的损伤中的生物学作用。共免疫沉淀和泛素化实验分析了 USP38 和 MCT1 之间的相互作用以及 MCT1 去泛素化的调控。通过基因编辑验证了MCT1在乳酸代谢和PM2.5诱导的细胞凋亡中的作用。蛋白质组学揭示了 USP38 调控细胞凋亡的潜在机制：结果：我们的研究结果表明，PM2.5 暴露诱导乳酸积累，导致细胞凋亡和肺损伤。USP38 通过去泛素化稳定了 MCT1 的表达，促进了乳酸的输出，减少了乳酸积累导致的细胞凋亡和肺损伤。从机理上讲，PM2.5 增加了乳酸的产生，抑制了 AKT/mTOR 通路的激活，促进了细胞凋亡和肺损伤。USP38 通过 MCT1 促进乳酸输出，激活 AKT/mTOR 通路，减轻 PM2.5 引起的肺损伤：结论：USP38 通过 MCT1 介导的乳酸输出促进 AKT/mTOR 通路活化，从而减少乳酸积累，减轻 PM2.5 引发的肺损伤。这些发现揭示了 PM2.5 相关肺损伤的新机制，并突出了潜在的治疗靶点。

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来源期刊

Journal of Clinical Laboratory Analysis 医学-医学实验技术

CiteScore

5.60

自引率

7.40%

发文量

584

审稿时长

6-12 weeks

期刊介绍： Journal of Clinical Laboratory Analysis publishes original articles on newly developing modes of technology and laboratory assays, with emphasis on their application in current and future clinical laboratory testing. This includes reports from the following fields: immunochemistry and toxicology, hematology and hematopathology, immunopathology, molecular diagnostics, microbiology, genetic testing, immunohematology, and clinical chemistry.