This study mainly explored the role of nicorandil in regulating ferroptosis and alleviating septic cardiomyopathy through toll-like receptor (TLR) 4/solute carrier family 7 member 11 (SLC7A11) signaling pathway. Twenty-four male SD rats were randomly divided into control, Nic (nicorandil), LPS (lipopolysaccharide), and LPS + Nic groups and given echocardiography. A detection kit was applied to measure the levels of lactic dehydrogenase (LDH), cardiac troponin I (cTnI), and creatine kinase-MB (CK-MB); HE staining and the levels of glutathione (GSH), malondialdehyde (MDA), total iron, and Fe²⁺ of myocardial tissues were detected. Moreover, the expression of TLR4 and SLC7A11 were measured by qRT-PCR and the proteins regulating ferroptosis (TLR4, SLC7A11, GPX4, ACSL4, DMT1, Fpn, and TfR1) were checked by western blot. Myocardial cells (H9C2) were induced with lipopolysaccharide (LPS) and transfected with si-TLR4 or SLC7A11-OE. Then, the viability, ferroptosis, and TLR4/SLC7A11 signaling pathway of cells were examined. Nicorandil could significantly increase left ventricular (LV) ejection fraction (LVEF) while reduce LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV). Also, it greatly reduced the levels of LDH, cTnI, and CK-MB; alleviated the pathological changes of myocardial injury; notably decreased MDA, total iron, and Fe²⁺ levels in myocardial tissues; and significantly increased GSH level. Besides, nicorandil obviously raised protein levels of GPX4, Fpn, and SLC7A11, and decreased protein levels of ACSL4, DMT1, TfR1, and TLR4. After knockdown of TLR4 or overexpression of SLC7A11, the inhibition effect of nicorandil on ferroptosis was strengthened in LPS-induced H9C2 cells. Therefore, nicorandil may regulate ferroptosis through TLR4/SLC7A11 signaling, thereby alleviating septic cardiomyopathy.

本研究主要探讨尼可地尔通过Toll样受体（TLR）4/溶质载体家族7成员11（SLC7A11）信号通路调节铁死亡、缓解脓毒症心肌病的作用。24只雄性SD大鼠随机分为对照组、Nic（尼可地尔）组、LPS（脂多糖）组和LPS+Nic组，并进行超声心动图检查。采用检测试剂盒测定乳酸脱氢酶（LDH）、心肌肌钙蛋白I（cTnI）、肌酸激酶MB（CK-MB）水平；检测心肌组织HE染色及谷胱甘肽（GSH）、丙二醛（MDA）、总铁、Fe~( ^2+)水平。此外，通过qRT-PCR测量TLR4和SLC7A11的表达，并通过蛋白质印迹检查调节铁死亡的蛋白（TLR4、SLC7A11、GPX4、ACSL4、DMT1、Fpn和TfR1）。用脂多糖（LPS）诱导心肌细胞（H9C2）并用si-TLR4或SLC7A11-OE转染。然后，检查细胞的活力、铁死亡和TLR4/SLC7A11信号通路。尼可地尔可显着增加左心室（LV）射血分数（LVEF），同时降低左心室舒张末期容积（LVEDV）和左心室收缩末期容积（LVESV）。此外，它还大大降低了 LDH、cTnI 和 CK-MB 的水平；减轻心肌损伤的病理变化；显着降低心肌组织中的MDA、总铁和Fe ^2+水平；并显着提高 GSH 水平。此外，尼可地尔明显升高GPX4、Fpn和SLC7A11的蛋白水平，降低ACSL4、DMT1、TfR1和TLR4的蛋白水平。在LPS诱导的H9C2细胞中，敲低TLR4或过表达SLC7A11后，尼可地尔对铁死亡的抑制作用增强。因此，尼可地尔可能通过TLR4/SLC7A11信号调节铁死亡，从而缓解脓毒症心肌病。