Amorphous silica nanoparticles (SiNPs) have been gradually proven to threaten cardiac health, but pathogenesis has not been fully elucidated. Ferroptosis is a newly defined form of programmed cell death that is implicated in myocardial diseases. Nevertheless, its role in the adverse cardiac effects of SiNPs has not been described. We first reported the induction of cardiomyocyte ferroptosis by SiNPs in both in vivo and in vitro. The sub-chronic exposure to SiNPs through intratracheal instillation aroused myocardial injury, characterized by significant inflammatory infiltration and collagen hyperplasia, accompanied by elevated CK-MB and cTnT activities in serum. Meanwhile, the activation of myocardial ferroptosis by SiNPs was certified by the extensive iron overload, declined FTH1 and FTL, and lipid peroxidation. The correlation analysis among detected indexes hinted ferroptosis was responsible for the SiNPs-aroused myocardial injury. Further, in vitro tests, SiNPs triggered iron overload and lipid peroxidation in cardiomyocytes. Concomitantly, altered expressions of TfR, DMT1, FTH1, and FTL indicated dysregulated iron metabolism of cardiomyocytes upon SiNP stimuli. Also, shrinking mitochondria with ridge fracture and ruptured outer membrane were noticed. To note, the ferroptosis inhibitor Ferrostatin-1 could effectively alleviate SiNPs-induced iron overload, lipid peroxidation, and myocardial cytotoxicity. More importantly, the mechanistic investigations revealed miR-125b-2-3p-targeted HO-1 as a key player in the induction of ferroptosis by SiNPs, probably through regulating the intracellular iron metabolism to mediate iron overload and ensuing lipid peroxidation. Our findings firstly underscored the fact that ferroptosis mediated by miR-125b-2-3p/HO-1 signaling was a contributor to SiNPs-induced myocardial injury, which could be of importance to elucidate the toxicity and provide new insights into the future safety applications of SiNPs-related nano products.

中文翻译：

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二氧化硅纳米粒子通过 miR-125b-2-3p/HO-1 信号传导诱导心肌细胞损伤

无定形二氧化硅纳米颗粒（SiNPs）已逐渐被证明会威胁心脏健康，但其发病机制尚未完全阐明。铁死亡是一种新定义的程序性细胞死亡形式，与心肌疾病有关。然而，其在 SiNPs 心脏不良反应中的作用尚未被描述。我们首次报道了 SiNPs 在体内和体外诱导心肌细胞铁死亡的情况。通过气管内滴注亚慢性暴露于 SiNPs 会引起心肌损伤，其特征是明显的炎症浸润和胶原增生，并伴有血清中 CK-MB 和 cTnT 活性升高。同时，广泛的铁过载、FTH1和FTL下降以及脂质过氧化证明了SiNPs对心肌铁死亡的激活。检测指标之间的相关性分析提示铁死亡是SiNPs引起的心肌损伤的原因。此外，在体外测试中，SiNPs 引发了心肌细胞中的铁过载和脂质过氧化。与此同时，TfR、DMT1、FTH1 和 FTL 表达的改变表明 SiNP 刺激后心肌细胞铁代谢失调。此外，还注意到线粒体收缩、脊断裂和外膜破裂。值得注意的是，铁死亡抑制剂Ferrostatin-1可以有效减轻SiNPs引起的铁过载、脂质过氧化和心肌细胞毒性。更重要的是，机制研究表明，miR-125b-2-3p 靶向的 HO-1 在 SiNP 诱导铁死亡中发挥着关键作用，可能是通过调节细胞内铁代谢来介导铁过载和随后的脂质过氧化。我们的研究结果首先强调了这样一个事实，即 miR-125b-2-3p/HO-1 信号介导的铁死亡是 SiNPs 诱导的心肌损伤的一个因素，这对于阐明毒性并为未来的安全应用提供新的见解可能很重要SiNPs相关的纳米产品。