m6A修饰的ATF4通过Sestrin2/GSK3β轴调节葡萄糖/脂质代谢，以减轻心肌缺血再灌注损伤
{"_":"mA-modified ATF4 regulates glucose/lipid metabolism via the Sestrin2/GSK3β axis to alleviate myocardial ischemia-reperfusion injury.","sup":["6"]}
摘要(中文译文)
心肌缺血再灌注损伤（MIRI）是心血管疾病治疗中的关键并发症，其发病机制与线粒体功能障碍及糖脂代谢失衡密切相关。本研究旨在探讨MIRI中糖脂代谢的分子机制并寻找潜在治疗靶点。通过生物信息学分析鉴定与MIRI相关的关键基因和预后生物标志物，并采用HL-1心肌细胞缺氧/复氧（H/R）模型模拟MIRI的病理过程。利用RNA干扰技术敲低ATF4，并通过生物信息学分析鉴定参与mA甲基化的关键分子。进一步探讨RBM15介导的ATF4 mRNA稳定性调控机制。采用流式细胞术、线粒体膜电位及ATP检测评估细胞凋亡、葡萄糖摄取、脂肪酸氧化及线粒体功能。生物信息学分析及HL-1心肌细胞H/R模型实验显示，ATF4在MIRI中高表达。敲低ATF4加重了H/R诱导的细胞凋亡和代谢紊乱。mA甲基转移酶RBM15通过甲基化调控ATF4 mRNA的稳定性和表达。进一步研究表明，ATF4上调Sestrin2抑制GSK3β活性，从而维持线粒体膜电位和ATP生成，促进葡萄糖摄取并增强脂肪酸氧化。本研究首次揭示了mA修饰的ATF4-Sestrin2/GSK3β信号轴通过双重调控糖脂代谢稳态和线粒体能量供应缓解MIRI的分子机制，阐明了RBM15介导的mA表观遗传修饰在该过程中的桥梁作用。这些发现为靶向代谢重编程治疗MIRI提供了新策略，并提示ATF4可作为干预靶点。
Abstract
Myocardial ischemia-reperfusion injury (MIRI) is a critical complication in the treatment of cardiovascular diseases, and its pathogenesis is closely associated with mitochondrial dysfunction and the imbalance of glucose/lipid metabolism. This study aims to investigate the molecular mechanisms underlying glucose/lipid metabolism in MIRI and identify potential therapeutic targets. Key genes and prognostic biomarkers related to MIRI were identified through bioinformatics analysis, and a hypoxia/reoxygenation (H/R) model using HL-1 cardiomyocytes was employed to simulate the pathological process of MIRI. RNA interference was used to knock down ATF4, and bioinformatics analysis identified key molecules involved in mA methylation. The regulatory mechanism of ATF4 mRNA stability mediated by RBM15 was further explored. Flow cytometry, mitochondrial membrane potential, and ATP assays were conducted to evaluate cell apoptosis, glucose uptake, fatty acid oxidation, and mitochondrial function. Bioinformatics analysis and the H/R model experiments in HL-1 cardiomyocytes revealed that ATF4 was highly expressed in MIRI. Knockdown of ATF4 exacerbated H/R-induced cell apoptosis and metabolic disturbances. mA methyltransferase RBM15 modulated the stability and expression of ATF4 mRNA through methylation. Further investigation showed that ATF4 upregulates Sestrin2 to inhibit GSK3β activity, thereby maintaining mitochondrial membrane potential and ATP production, promoting glucose uptake, and enhancing fatty acid oxidation. This study is the first to reveal the molecular mechanism by which the mA modified ATF4-Sestrin2/GSK3β signaling axis alleviates MIRI through dual regulation of glucose/lipid metabolism homeostasis and mitochondrial energy supply. It elucidates the bridging role of RBM15-mediated mA epigenetic modification in this process. These findings provide a new strategy for targeting metabolic reprogramming in MIRI therapy and suggest that ATF4 may serve as an intervention target.
如何引用
AMA
Jie Wu, Jian Tong, Fen Zhang, Xingxing Li, Xizhi Liu, Yang Dong. {"_":"mA-modified ATF4 regulates glucose/lipid metabolism via the Sestrin2/GSK3β axis to alleviate myocardial ischemia-reperfusion injury.","sup":["6"]}. Journal of cardiothoracic surgery. 2026; doi:10.1186/s13019-026-04282-8.
APA
Jie Wu, Jian Tong, Fen Zhang, Xingxing Li, Xizhi Liu, Yang Dong (2026). {"_":"mA-modified ATF4 regulates glucose/lipid metabolism via the Sestrin2/GSK3β axis to alleviate myocardial ischemia-reperfusion injury.","sup":["6"]}. Journal of cardiothoracic surgery. https://doi.org/10.1186/s13019-026-04282-8
GB/T 7714
Jie Wu, Jian Tong, Fen Zhang, Xingxing Li, Xizhi Liu, Yang Dong. {"_":"mA-modified ATF4 regulates glucose/lipid metabolism via the Sestrin2/GSK3β axis to alleviate myocardial ischemia-reperfusion injury.","sup":["6"]}[J]. Journal of cardiothoracic surgery, 2026 doi:10.1186/s13019-026-04282-8.
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