Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167307. doi: 10.1016/j.bbadis.2024.167307. Epub 2024 Jun 17.
Sepsis is a global health challenge that results in systemic inflammation, oxidative stress, and multi-organ dysfunction, with the heart being particularly susceptible. This study aimed to elucidate the effect of FTO, a key regulator in mA methylation in septic cardiomyopathy, and its potential therapeutic implications. Cellular and animal models of septic myocardial injury were established. Moreover, it was revealed that ferroptosis, which is a form of programmed necrosis occurring with iron dependence, was activated within cardiomyocytes during septic conditions. The overexpression of FTO-suppressed ferroptosis alleviated heart inflammation and dysfunction and improved survival rates in vivo. However, the protective effects of FTO were attenuated by the overexpression of BACH1, which is a molecule negatively correlated with FTO. Mechanistically, FTO modulated the mA modification of BACH1, suggesting a complex interplay in the regulation of cardiomyocyte damage and sepsis. Our findings reveal the potential of targeting the FTO/BACH1 axis and ferroptosis inhibitors as therapeutic strategies for sepsis-induced cardiac injuries.
脓毒症是一种全球性的健康挑战，可导致全身炎症、氧化应激和多器官功能障碍，其中心脏尤其容易受到影响。本研究旨在阐明 FTO（在 mA 甲基化中起关键调节作用的基因）在脓毒性心肌病中的作用及其潜在的治疗意义。建立了脓毒症心肌损伤的细胞和动物模型。此外，研究揭示了在脓毒症条件下，铁依赖性的程序性坏死形式——铁死亡，在心肌细胞中被激活。FTO 的过表达抑制铁死亡，减轻了心脏炎症和功能障碍，并提高了体内的存活率。然而，FTO 的保护作用被与 FTO 呈负相关的分子 BACH1 的过表达所减弱。从机制上讲，FTO 调节 BACH1 的 mA 修饰，表明在调节心肌损伤和脓毒症方面存在复杂的相互作用。我们的研究结果揭示了靶向 FTO/BACH1 轴和铁死亡抑制剂作为治疗脓毒症引起的心脏损伤的潜在策略。
