Zhang Yuan, Yang Zhi-Chang, Zhou Qian-Hua, Geng Zhen-Yang, Huang Kai-Jun, Yang Yang, Yuan Hao-Xiang, Shen Pu
Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China.
Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
J Thorac Dis. 2025 Aug 31;17(8):6045-6065. doi: 10.21037/jtd-2025-358. Epub 2025 Aug 27.
Ex vivo lung perfusion (EVLP) serves as a vital platform for donor lung assessment and repair in transplantation. Although lipid metabolism plays a crucial role in pulmonary homeostasis and undergoes alterations during EVLP, the precise regulatory mechanisms linking metabolic changes to immune modulation remain poorly understood. This study aimed to identify key lipid metabolism-related genes governing immune microenvironment remodeling during EVLP and to validate their diagnostic and therapeutic potential.
We analyzed transcriptomic profiles from human donor lungs before and after EVLP using datasets GSE127057 (discovery cohort) and GSE127055 (validation cohort). A comprehensive analytical framework was implemented, incorporating weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks, and three machine learning algorithms including least absolute shrinkage and selection operator (LASSO) regression, Random Forest (RF), and eXtreme Gradient Boosting (XGBoost) to identify key lipid metabolism-related genes. Immune cell infiltration patterns were characterized using established computational methods, with subsequent validation in an EVLP model of C57BL/6J wild-type mice.
Analysis of GSE127057 revealed 656 differentially expressed genes (DEGs) post-EVLP. Through integrative bioinformatics approaches, three lipid metabolism-related hub genes (, , ) were identified as consistently upregulated. These genes demonstrated significant positive correlations with resting natural killer (NK) cell populations and negative associations with activated NK cells. The diagnostic potential of these biomarkers was confirmed through receiver operating characteristic (ROC) analysis, achieving an area under curve (AUC) of 0.986 in the discovery cohort (GSE127057) and 0.922 in the independent validation cohort (GSE127055). Experimental validation in murine EVLP models recapitulated the significant upregulation of all three hub genes.
This study establishes UGCG, SAMD8, and MED26 as central regulators of lipid metabolism during EVLP, with their expression patterns correlating with NK cell functional states. These findings provide mechanistic insights into metabolic-immune interactions during donor lung preservation and identify potential biomarkers for clinical monitoring and therapeutic targeting.
体外肺灌注（EVLP）是移植中供体肺评估和修复的重要平台。尽管脂质代谢在肺稳态中起关键作用，且在EVLP过程中会发生改变，但将代谢变化与免疫调节联系起来的精确调控机制仍知之甚少。本研究旨在确定在EVLP过程中控制免疫微环境重塑的关键脂质代谢相关基因，并验证其诊断和治疗潜力。
我们使用数据集GSE127057（发现队列）和GSE127055（验证队列）分析了人类供体肺在EVLP前后的转录组谱。实施了一个综合分析框架，包括加权基因共表达网络分析（WGCNA）、蛋白质-蛋白质相互作用（PPI）网络以及三种机器学习算法，即最小绝对收缩和选择算子（LASSO）回归、随机森林（RF）和极端梯度提升（XGBoost），以识别关键的脂质代谢相关基因。使用既定的计算方法对免疫细胞浸润模式进行表征，并随后在C57BL/6J野生型小鼠的EVLP模型中进行验证。
对GSE127057的分析显示，EVLP后有656个差异表达基因（DEG）。通过综合生物信息学方法，确定了三个脂质代谢相关的枢纽基因（UGCG、SAMD8、MED26）持续上调。这些基因与静息自然杀伤（NK）细胞群体呈显著正相关，与活化NK细胞呈负相关。通过受试者工作特征（ROC）分析证实了这些生物标志物的诊断潜力，在发现队列（GSE127057）中曲线下面积（AUC）为0.986，在独立验证队列（GSE127055）中为0.922。在小鼠EVLP模型中的实验验证重现了所有三个枢纽基因的显著上调。
本研究确定UGCG、SAMD8和MED26是EVLP期间脂质代谢的核心调节因子，它们的表达模式与NK细胞功能状态相关。这些发现为供体肺保存期间的代谢-免疫相互作用提供了机制性见解，并确定了用于临床监测和治疗靶点的潜在生物标志物。
