在重症急性胰腺炎中,m6A 激活的 BACH1 通过表观遗传抑制 HSPB1 而加剧铁蛋白沉积症

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-09-16 DOI:10.1002/ddr.22256
Fawei Zhou, Dezhong Li, Chang Liu, Can Li, Kaili Li, Lu Shi, Fachun Zhou
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引用次数: 0

摘要

重症急性胰腺炎(SAP)以胰腺急性炎症为特征。转录因子 BTB 和 CNC 同源物 1(BACH1)与多种生物过程有关,包括氧化应激、细胞凋亡和细胞周期调节。然而,其在 SAP 发病机制中的参与程度仍相对较低。在本研究中,我们的数据表明,在 SAP 患者、细胞和动物模型中,BACH1 水平显著升高,而热休克蛋白 B1(HSPB1)表达减弱。机理实验验证了 BACH1 是 HSPB1 的转录抑制剂。此外,HPDE6-C7细胞在体外受到cerulein(Cer)和LPS的刺激,以模拟SAP的病理阶段。在 SAP 细胞模型中,耗竭 BACH1 能显著提高细胞存活率,减轻氧化应激、铁蛋白沉着和炎症反应。然而,在同时抑制 HSPB1 后,这些变化被显著逆转。动物实验结果证实,BACH1 的缺失会减轻胰腺损伤、炎症反应和铁蛋白沉积,但这些作用会因 HSPB1 的沉默而减弱。总之,这些研究结果阐明了 BACH1 的过度表达会通过转录抑制 HSBP1 来促进铁蛋白沉积和炎症反应,从而加剧 SAP 的进展。
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m6A-activated BACH1 exacerbates ferroptosis by epigenetic suppression HSPB1 in severe acute pancreatitis

Severe acute pancreatitis (SAP) is characterized by acute inflammation of the pancreas. The transcription factor BTB and CNC homology 1 (BACH1) has been implicated in various biological processes, including oxidative stress, apoptosis, and cell cycle regulation. However, its involvement in the pathogenesis of SAP remains relatively understudied. In the present work, our data demonstrated that BACH1 level was significantly increased in SAP patients, cellular, and animal models, while heat shock protein B1 (HSPB1) expression was weakened. Mechanistic assays validated that BACH1 acted as a transcriptional inhibitor of HSPB1. Moreover, HPDE6-C7 cells were stimulated with cerulein (Cer) and LPS to mimic the pathological stages of SAP in vitro. Depletion of BACH1 remarkably improved cell survival and alleviated the oxidative stress, ferroptosis, and inflammatory responses in SAP cell models. However, these changes were dramatically reversed upon co-inhibition of HSPB1. Animal findings confirmed that loss of BACH1 decreased pancreatic injury, inflammatory responses, and ferroptosis, but these effects were weakened by HSPB1 silence. Overall, these findings elucidate that the overexpression of BACH1 favors the ferroptosis and inflammation by transcriptionally inhibiting HSBP1, thereby exacerbating SAP progression.

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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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