Acute liver failure (ALF) is a life-threatening disease, but its pathogenesis is not fully understood. NETosis is a novel mode of cell death. Although the formation of neutrophil extracellular traps (NETs) has been found in various liver diseases, the specific mechanism by which NETosis regulates the development of ALF is unclear. In this article, we explore the role and mechanism of NETosis in the pathogenesis of ALF. Clinically, we evaluated NETs-related markers in the liver and peripheral neutrophils of patients with ALF. In in vitro experiments, HL-60 cells were first induced to differentiate into neutrophil-like cells (dHL-60 cells) with dimethyl sulfoxide (DMSO). NETs were formed by inducing dHL-60 cells with PMA. In in vivo experiments, the ALF model in mice was established with LPS/d-gal, and the release of NETs was detected by immunofluorescence staining and western blotting. Finally, the acetylation levels of IDH1 and MDH1 were detected in dHL-60 cells and liver samples by immunoprecipitation. Clinically, increased release of NETs in liver tissue was observed in patients with ALF, and NETs formation was detected in neutrophils from patients with liver failure. In dHL-60 cells, mutations at IDH1-K93 and MDH1-K118 deacetylate IDH1 and MDH1, which promotes the formation of NETs. In a mouse model of ALF, deacetylation of IDH1 and MDH1 resulted in NETosis and promoted the progression of acute liver failure. Deacetylation of IDH1 and MDH1 reduces their activity and promotes the formation of NETs. This change aggravates the progression of acute liver failure.

中文翻译：

---

IDH1/MDH1 去乙酰化通过调节 NETosis 促进急性肝衰竭

急性肝衰竭（ALF）是一种危及生命的疾病，但其发病机制尚不完全清楚。NETosis 是一种新的细胞死亡模式。尽管在多种肝脏疾病中发现了中性粒细胞胞外陷阱（NET）的形成，但NETosis调节ALF发生的具体机制尚不清楚。在本文中，我们探讨了 NETosis 在 ALF 发病机制中的作用和机制。临床上，我们评估了 ALF 患者肝脏和外周中性粒细胞中的 NETs 相关标志物。在体外实验中，首先用二甲亚砜（DMSO）诱导HL-60细胞分化为中性粒细胞样细胞（dHL-60细胞）。通过用 PMA 诱导 dHL-60 细胞形成 NET。在体内实验中，采用LPS/d-gal建立小鼠ALF模型，并通过免疫荧光染色和western blotting检测NETs的释放。最后，通过免疫沉淀法检测dHL-60细胞和肝脏样本中IDH1和MDH1的乙酰化水平。临床上，在 ALF 患者中观察到肝组织中 NET 的释放增加，并且在肝功能衰竭患者的中性粒细胞中检测到 NET 的形成。在 dHL-60 细胞中，IDH1-K93 和 MDH1-K118 的突变会使 IDH1 和 MDH1 去乙酰化，从而促进 NET 的形成。在 ALF 小鼠模型中，IDH1 和 MDH1 去乙酰化导致 NETosis 并促进急性肝衰竭的进展。IDH1 和 MDH1 的去乙酰化降低了它们的活性并促进 NET 的形成。这种变化加剧了急性肝衰竭的进展。