Chen Qian, Wang Yina, Wang Jiafu, Ouyang Xiaolan, Zhong Junlin, Huang Yao, Huang Zhuoshan, Zheng Benrong, Peng Long, Tang Xixiang, Li Suhua
Department of Cardiovascular Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
VIP medical service center, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Antioxid Redox Signal. 2025 Feb;42(4-6):184-198. doi: 10.1089/ars.2023.0510. Epub 2024 Aug 1.
Lipotoxicity is a well-established contributor to cardiomyocyte death and heart damage, with ferroptosis being identified as a crucial death mode in cardiomyocyte disease. This study aims to explore the potential role and mechanism of ferroptosis in lipotoxicity-induced myocardial injury. Eight-week high-fat diet (HFD) Sprague-Dawley rat and H9c2 cardiomyocytes treated with palmitic acid (PA) were established for an and lipotoxic model. Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) were used to inhibit ferroptosis. Myocardial-specific stimulator of interferon genes (STING) knockdown rat () with HFD was further introduced. Rat cardiac structure and function, cell viability, the level of lipid peroxidation, malondialdehyde (MDA), glutathione (GSH), mitochondrial function, ferroptosis-related proteins, and STING pathway-related proteins in H9c2 cells/myocardium were detected. HFD rats with a ferroptosis inhibitor showed improved cardiac structure and function, reduced lipid peroxidation, and restored GSH, which was further confirmed in H9c2 cell. The time-dependent activation of the STING pathway following PA stimulation was observed. Knockdown of the expression of STING could reduce PA-induced cell death, lipid peroxidation, and MDA levels while restoring the GSH. In addition, both HFD rats and HFD rats with systematic inhibition by the STING inhibitor exhibited mitigating lipotoxicity-induced myocardial ferroptosis and reducing myocardial injury. These findings suggest that lipotoxicity can induce ferroptosis in cardiomyocytes through the activation of the STING pathway, providing new targets and strategies for the treatment of lipotoxicity cardiomyopathy. 42, 184-198.
脂毒性是心肌细胞死亡和心脏损伤的一个公认因素，铁死亡被认为是心肌细胞疾病中的一种关键死亡模式。本研究旨在探讨铁死亡在脂毒性诱导的心肌损伤中的潜在作用及机制。建立了八周高脂饮食（HFD）的Sprague-Dawley大鼠模型以及用棕榈酸（PA）处理的H9c2心肌细胞模型，作为脂毒性模型。使用铁抑素-1（Fer-1）和脂氧素他汀-1（Lip-1）抑制铁死亡。进一步构建了心肌特异性干扰素基因刺激因子（STING）敲低的高脂饮食大鼠（）模型。检测了大鼠的心脏结构和功能、细胞活力、脂质过氧化水平、丙二醛（MDA）、谷胱甘肽（GSH）、线粒体功能、铁死亡相关蛋白以及H9c2细胞/心肌中的STING通路相关蛋白。使用铁死亡抑制剂的高脂饮食大鼠心脏结构和功能得到改善，脂质过氧化减少，GSH恢复，这在H9c2细胞中得到进一步证实。观察到PA刺激后STING通路的时间依赖性激活。敲低STING的表达可减少PA诱导的细胞死亡、脂质过氧化和MDA水平，同时恢复GSH。此外，STING抑制剂系统性抑制的高脂饮食大鼠和高脂饮食大鼠均表现出减轻脂毒性诱导的心肌铁死亡并减少心肌损伤。这些发现表明，脂毒性可通过激活STING通路诱导心肌细胞铁死亡，为脂毒性心肌病的治疗提供了新的靶点和策略。42, 184 - 198。
