环状RNA circDhx32通过与AdipoR1竞争的FOXO1结合促进小鼠心脏缺血再灌注损伤中的心脏炎症反应，这一成果由哈尔滨医科大学卞宇研究小组经过不懈努力而取得。2025年6月17日出版的《中国药理学报》杂志发表了这项成果。

在这项研究中，该课题组人员研究了circDhx32在I/R损伤进展中的调节作用。结扎左冠状动脉前降支（LAD） 45最小，然后血液再灌注24H或2周。在体外研究中，新生儿无母心室心肌细胞遭受缺氧再氧（H/R）攻击。CircDhx32在I/R处理的小鼠和H/R处理的心肌细胞中显著上调。心肌细胞特异性敲低circDhx32可改善心脏I/R损伤的病理结果，包括改善心功能、减少梗死面积和减少心脏损伤生物标志物的释放。在H/R后心肌细胞中也观察到circDhx32沉默的保护作用。课题组证明ALKBH5作为m⁶A去甲基化酶起作用，去除circDhx32的m⁶A修饰位点。减少m⁶A修饰抑制m⁶A读取器YTHDF2和YTHDC1的识别和结合，导致病理条件下circDhx32降解和核质输出减少。升高的circDhx32通过与FOXO1结合抑制AdipoR1的转录激活。相反，circDhx32缺乏减轻了I/R处理小鼠和H/R处理心肌细胞的炎症反应，包括mRNA表达水平降低和炎症细胞因子如IL-6、TNF-α和IL-1β的释放，可能通过调节AdipoR1-AMPK-NF-κB信号通路。综上所述，在病理条件下，ALKBH5与m⁶A读卡器YTHDF2和YTHDC1一起起到m⁶A擦除器的作用，促进circDhx32的高表达和核保留。CircDhx32通过靶向AdipoR1-AMPK-NF-κB信号通路调控心脏I/R损伤的炎症反应，该信号通路与AdipoR1竞争FOXO1。这些结果揭示了心脏缺血损伤的新机制，circDhx32有望成为缺血性心脏病早期干预的潜在治疗靶点。

据介绍，缺血性心脏病是人类死亡的一个重要原因，向受损心肌再供血可增加心脏I/R损伤的风险。环状RNA （circRNAs）在心血管疾病中发挥重要作用。

附：英文原文

Title: Circular RNA circDhx32 promotes cardiac inflammatory responses in mouse cardiac ischemia-reperfusion injury via binding to FOXO1 competed with AdipoR1

Author: Si, Wei, Wang, Chun-lei, Zeng, Ling-hua, Zhao, Qiao-yue, Xie, Ya-ting, Yang, Yang, Diao, Hong-tao, Song, Jing-lun, Wu, Han, Zhang, Feng, Wang, Zhuo, Kong, Xue, Jiang, Wei-tao, Zhang, Xin-yue, Lin, Ke-ying, Yao, Fang-ting, Xiong, Yu-ting, Pan, Teng-fei, Pang, Ping, Yang, Bao-feng, Bian, Yu

Issue&Volume: 2025-06-17

Abstract: Ischaemic heart disease is an important cause of death in humans, and resupply of blood to damaged myocardium can exacerbate the risk of cardiac I/R injury. Circular RNAs (circRNAs) play an important role in cardiovascular disease. In this study we investigated the regulatory role of circDhx32 in the progression of I/R injury. Cardiac I/R model was established in mice by ligating the left anterior descending coronary artery (LAD) for 45min, followed by blood reperfusion for 24h or 2 weeks. For in vitro study, neonatal mouse ventricular cardiomyocytes were subjected to hypoxia-reoxygenation (H/R) assault. CircDhx32 was significantly upregulated in I/R-treated mice and H/R-treated cardiomyocytes. Cardiomyocyte-specific knockdown of circDhx32 ameliorated the pathological outcomes of cardiac I/R injury including improved cardiac function, reduced infarct size and reduced release of cardiac injury biomarkers. The protective effects of circDhx32 silencing were also observed in cardiomyocytes after H/R. We demonstrated that ALKBH5 functioned as an m6A demethylase, removing the m6A modification sites of circDhx32. Reduced m6A modification inhibited recognition and binding by the m6A readers YTHDF2 and YTHDC1, leading to circDhx32 degradation and diminished nucleoplasmic export under pathological conditions. Elevated circDhx32 inhibited the transcriptional activation of AdipoR1 by binding to FOXO1. Conversely, circDhx32 deficiency alleviated the inflammatory responses in I/R-treated mice and H/R-treated cardiomyocytes including decreased mRNA expression levels and release of inflammatory cytokines such as IL-6, TNF-α and IL-1β potentially through modulation of the AdipoR1-AMPK-NF-κB signaling pathway. In conclusion, ALKBH5 acted as m6A eraser accompanied by the m6A readers YTHDF2 and YTHDC1 to promote high expression and nuclear retention of circDhx32 under pathological conditions. CircDhx32 regulated the inflammatory responses to cardiac I/R injury by targeting the AdipoR1-AMPK-NF-κB signaling pathway, which competed with AdipoR1 for FOXO1. These results reveal a novel mechanism underlying cardiac ischaemic injury, and circDhx32 is expected to be a potential therapeutic target for early intervention in ischaemic cardiac disease.

DOI: 10.1038/s41401-025-01593-9

Source: https://www.nature.com/articles/s41401-025-01593-9