单细胞与批量RNA测序揭示MCL1作为肝脏缺血再灌注损伤中线粒体功能的关键调控因子

摘要(中文译文)

肝脏缺血再灌注损伤（LIRI）是肝移植及外科手术后的重要并发症，由于可用治疗选择有限，目前仍缺乏充分的应对手段。本研究旨在阐明与LIRI相关的适应不良免疫反应和线粒体功能障碍背后的关键调控因子。通过整合多个微阵列数据集（GSE12720、GSE112713、GSE23649和GSE151648）及单细胞RNA测序（scRNA-seq）数据（GSE171539），我们采用加权基因共表达网络分析（WGCNA）并结合四种机器学习算法（SVM、LASSO、RF和XGBoost）来识别核心基因。我们的分析突显了MCL1作为与线粒体功能相关的关键核心基因，其在LIRI中表达水平显著升高，并具有较强的诊断准确性。进一步的单细胞分析揭示了MCL1在内皮细胞（ECs）和巨噬细胞（MCs）中的特异性富集，同时鉴定出一个新的巨噬细胞亚群（CSF1RIL-1BMCL1），该亚群具有促炎和促生存的双重表型。这一发现提示涉及NF-κB、凋亡和细胞因子信号等关键通路的细胞间串扰增强，而MCL1的计算机模拟敲除显著破坏了免疫相关基因网络。验证研究证实了小鼠LIRI模型中MCL1的上调及该巨噬细胞亚群的存在。总之，我们的研究结果将MCL1定位为连接LIRI中免疫炎症与线粒体功能障碍的重要调控因子，提出其作为管理该病症的有前景的诊断生物标志物和治疗靶点，但其最佳治疗方向仍需进一步研究。

Abstract

Liver ischemia-reperfusion injury (LIRI), a significant complication following liver transplantation and surgical procedures, remains inadequately addressed due to the limited therapeutic options available. This study aims to elucidate the pivotal regulators underlying the maladaptive immune responses and mitochondrial dysfunction associated with LIRI. By integrating multiple microarray datasets (GSE12720, GSE112713, GSE23649, and GSE151648) and single-cell RNA sequencing (scRNA-seq) data (GSE171539), we employed weighted gene co-expression network analysis (WGCNA) alongside four machine learning algorithms (SVM, LASSO, RF, and XGBoost) to identify hub genes. Our analyzes highlighted MCL1 as a critical hub gene linked to mitochondrial function, exhibiting significantly elevated expression levels in LIRI, coupled with strong diagnostic accuracy. Further single-cell analysis revealed MCL1's specific enrichment in endothelial cells (ECs) and macrophages (MCs), along with the identification of a novel macrophage subset (CSF1RIL-1BMCL1) characterized by a dual pro-inflammatory and pro-survival phenotype. This finding suggests enhanced intercellular crosstalk involving key pathways such as NF-κB, apoptosis, and cytokine signaling, while in silico knockout of MCL1 markedly disrupted immune-related gene networks. Validation studies confirmed MCL1 upregulation and the presence of the macrophage subset in a murine LIRI model. In conclusion, our findings position MCL1 as a vital regulator linking immune inflammation and mitochondrial dysfunction in LIRI, proposing it as a promising diagnostic biomarker and therapeutic target for managing this condition, though its optimal therapeutic direction requires further investigation.

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