杂志名称：International Journal of Biological Sciences
影响因子：8.2
文章题目：microRNA-130b-3p Attenuates Septic Cardiomyopathy by Regulating the AMPK/mTOR Signaling Pathways and Directly Targeting ACSL4 against Ferroptosis
DOI: 10.7150/ijbs.82287
第一作者：Zhen Qi , Ruhui Liu , Haining Ju , Mengxi Huang , Zhe Li , Wei Li  , Yongyi Wang
作者单位：
上海交通大学医学院附属仁济医院
四川大学华西第二大学医院
上海中医药大学第七人民医院
南京鼓楼医院
引用YOBIBIO产品：
U96-5422E  Mouse cTnI ELISA Kit
U96-5379E  Mouse CK-MB ELISA Kit

文章摘要：
Ferroptosis is a newly identified type of programmed cell death that has been shown to contribute to the progression of septic cardiomyopathy. Although the role of miR-130b-3p as an oncogene that accelerates cancer progression by suppressing ferroptosis has been demonstrated, its role in the regulation of ferroptosis and cardiac injury in Lipopolysaccharide (LPS)-induced cardiomyopathy has not been fully clarified. In this study, we demonstrated that miR-130b-3p remarkably improved cardiac function and ameliorated morphological damage to heart tissue in LPS-induced mice. miR-130b-3p also improved cell viability and mitochondrial function and reduced the production of lipid ROS and ferroptosis in LPS-treated H9c2 cells. In addition, miR-130b-3p significantly upregulated GPX4 expression and suppressed ACSL4 activity in LPS-induced mouse heart tissue and H9c2 cells. Mechanistically, we used database analysis to locate miR-130b-3p and confirmed its inhibitory effects on the ferroptosis-related gene ACSL4 and autophagy-related gene PRKAA1 using a dual-luciferase reporter assay. In addition, we found that miR-130b-3p inhibited the activation of autophagy by downregulating the expression of the AMPK/mTOR signaling pathway. Meanwhile, our results show that RAPA (an autophagy activator) reverses the protective effect of miR-130b-3p mimic against LPS-induced ferroptosis, while CQ (an autophagy inhibitor) plays a facilitative role, suggesting that miR-130b-3p plays an important role in the development of ferroptosis by regulating autophagy in vitro. The findings reveal a novel function of miR-130b-3p in attenuating ferroptosis in cardiomyocytes, providing a new therapeutic target for ameliorating septic cardiomyopathy injury.

铁死亡是一种新发现的程序性细胞死亡类型，已被证明有助于脓毒症心肌病的进展。尽管miR-130b-3p作为癌基因通过抑制铁死亡加速癌症进展的作用已被证明，但其在脂多糖（LPS）诱导的心肌病中铁死亡和心脏损伤的调节中的作用尚未完全阐明。在这项研究中，我们证明 miR-130b-3p 显着改善了 LPS 诱导的小鼠的心脏功能并改善了心脏组织的形态损伤。miR-130b-3p 还可以改善 LPS 处理的 H9c2 细胞中的细胞活力和线粒体功能，并减少脂质 ROS 的产生和铁死亡。此外，在LPS诱导的小鼠心脏组织和H9c2细胞中，miR-130b-3p显着上调GPX4表达并抑制ACSL4活性。从机制上讲，我们使用数据库分析来定位 miR-130b-3p，并使用双荧光素酶报告基因测定证实其对铁死亡相关基因 ACSL4 和自噬相关基因 PRKAA1 的抑制作用。此外，我们发现miR-130b-3p通过下调AMPK/mTOR信号通路的表达来抑制自噬的激活。同时，我们的结果表明，RAPA（一种自噬激活剂）逆转了 miR-130b-3p 模拟物对 LPS 诱导的铁死亡的保护作用，而 CQ（一种自噬抑制剂）则起促进作用，这表明 miR-130b-3p 发挥着促进作用。通过体外调节自噬在铁死亡的发展中发挥重要作用。研究结果揭示了 miR-130b-3p 在减轻心肌细胞铁死亡方面的新功能，为改善脓毒症心肌病损伤提供了新的治疗靶点。