Hong Jia, Xu Hongjiao, Yu Lang, Yu Zhuang, Chen Xiangyuan, Meng Zhipeng, Zhu Jiali, Li Jinbao, Zhu Minmin
Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Anesthesiology, Shanghai General Hospital of Nangjing Medical University, Shanghai, China.
Cell Death Differ. 2025 Sep 23. doi: 10.1038/s41418-025-01587-4.
Diabetic nephropathy (DN) is the primary cause of end-stage renal disease worldwide. Recent studies have revealed that lactate-mediated histone lactylation, which functions as a novel epigenetic modification, is involved in the occurrence and development of diabetes-related complications. However, little is known about the role of lactyltransferase in DN. Alanyl-tRNA synthetase 1 (AARS1) was identified as a novel lactyltransferase that modulates histone H3-lysine-18 lactylation (H3K18la). In the present study, we determined whether AARS1-mediated H3K18la participates in the pathogenesis of DN. More importantly, we explored the potential mechanism involved. A mouse DN model consisting of both wild-type and alanyl-tRNA synthetase (AARS1) heterozygote (AARS1) mice was utilized in this study. Transcriptomic and lipidomic analyses, combined with a variety of molecular biological methodologies, were employed to elucidate the potential mechanism by which AARS1 regulates ferroptosis in DN. Our results indicated that the increases in AARS1 and H3K18la expression were involved in kidney dysfunction and renal cell death via the modulation of ferroptosis in the DN model. Moreover, AARS1 induced lipid peroxidation by increasing fatty acid elongase-5 (ELOVL5) transcription, ultimately contributing to ferroptosis induction. Furthermore, AARS1 interacted with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ELOVL5 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. In addition, we observed that AARS1 modulated the lactylation of both STAT1 and H3K18 to regulate ELOVL5 transcription, thus triggering ferroptosis. Inhibition of AARS1-induced lactylation via β-alanine attenuated ferroptosis in DN model mice and hyperglycaemic cells. The present study showed that AARS1 induced the lactylation of H3K18 and STAT1 to regulate ELOVL5 transcription, thus triggering ferroptosis in a diabetic nephropathy model.
糖尿病肾病（DN）是全球终末期肾病的主要原因。最近的研究表明，乳酸介导的组蛋白乳酰化作为一种新的表观遗传修饰，参与糖尿病相关并发症的发生和发展。然而，关于乳酰转移酶在DN中的作用知之甚少。丙氨酰-tRNA合成酶1（AARS1）被鉴定为一种新型乳酰转移酶，可调节组蛋白H3-赖氨酸-18乳酰化（H3K18la）。在本研究中，我们确定AARS1介导的H3K18la是否参与DN的发病机制。更重要的是，我们探索了其中涉及的潜在机制。本研究使用了由野生型和丙氨酰-tRNA合成酶（AARS1）杂合子（AARS1）小鼠组成的小鼠DN模型。采用转录组学和脂质组学分析，并结合多种分子生物学方法，以阐明AARS1调节DN中铁死亡的潜在机制。我们的结果表明，在DN模型中，AARS1和H3K18la表达的增加通过调节铁死亡参与了肾功能障碍和肾细胞死亡。此外，AARS1通过增加脂肪酸延长酶-5（ELOVL5）转录诱导脂质过氧化，最终导致铁死亡诱导。此外，AARS1与信号转导和转录激活因子1（STAT1）相互作用，共同调节ELOVL5转录。此外，用STAT1特异性抑制剂氟达拉滨治疗可延缓DN进展。此外，我们观察到AARS1调节STAT1和H3K18的乳酰化以调节ELOVL5转录，从而触发铁死亡。通过β-丙氨酸抑制AARS1诱导的乳酰化可减轻DN模型小鼠和高血糖细胞中的铁死亡。本研究表明，AARS1诱导H3K18和STAT1的乳酰化以调节ELOVL5转录，从而在糖尿病肾病模型中触发铁死亡。
