基于机器学习和实验验证筛选肾移植缺血-再灌注损伤中程序性细胞死亡的核心基因

Identification of core genes in programmed cell death during ischemia-reperfusion injury in kidney transplantation based on machine learning and experimental validation

    摘要
  • 摘要:
    目的 探讨肾移植缺血-再灌注损伤（IRI）的关键程序性细胞死亡（PCD）模式及核心基因。
    方法 从基因表达综合数据库获取肾移植相关数据集，筛选PCD相关差异基因，并基于非负矩阵分解算法对患者进行分型，阐明不同亚型的生物学功能及关键PCD模式。构建机器学习模型，结合单因素Cox回归分析与Kaplan-Meier生存曲线筛选肾移植IRI的PCD核心基因，并分析其与关键PCD模式的相关性。构建大鼠肾移植模型，采用苏木精-伊红染色、血清肌酐（Scr）和血尿素氮（BUN）评估肾移植IRI的严重程度，采用蛋白质免疫印迹法检测核心基因蛋白表达。
    结果 共筛选出14个PCD相关差异基因，将患者分为代谢型（亚型1）和炎症型（亚型2），其中亚型2激活细胞焦亡、坏死性凋亡、细胞凋亡以及免疫原性细胞死亡4种关键PCD模式。最优模型（XGBoost−CV:10 fold+Lasso−CV:10 fold）以及生存分析筛选出MCL1、BAG3和RHOB为肾移植IRI的PCD核心基因，其与关键PCD模式广泛相关。动物实验结果显示，与假手术组相比，模型组大鼠肾小管损伤加重；Scr和BUN水平显著升高，BAG3、RHOB和MCL1蛋白表达增多（均为P＜0.001）。
    结论 细胞焦亡、坏死性凋亡、细胞凋亡以及免疫原性细胞死亡作为关键PCD模式参与肾移植IRI的病理进程，MCL1、BAG3和RHOB可能作为其核心基因，成为肾移植IRI的潜在生物标志物及治疗靶点。

     

    Abstract:
    Objective To identify key patterns of programmed cell death (PCD) and core genes during ischemia-reperfusion injury (IRI) in kidney transplantation.
    Methods Kidney transplant datasets were obtained from gene expression database, and PCD-related differentially expressed genes were screened The non-negative matrix factorization algorithm was used to classify patients and analyze subtype-specific biological functions and key PCD patterns. Machine learning models combined with univariate Cox regression and Kaplan-Meier survival analysis were employed to identify core PCD genes during IRI in kidney transplantation and explore their correlation with key PCD patterns. A rat kidney transplant model was used to assess IRI severity through hematoxylin-eosin staining, serum creatinine (Scr), blood urea nitrogen (BUN), and Western blotting for key gene protein expression.
    Results Fourteen PCD-related genes were identified. Patients were classified into metabolic (subtype 1) and inflammatory (subtype 2) subtypes. Subtype 2 activated four key PCD patterns: pyroptosis, necroptosis, apoptosis, and immunogenic cell death. The optimal model (XGBoost-CV:10 fold+Lasso-CV:10 fold) and survival analysis identified MCL1, BAG3, and RHOB as core PCD genes during IRI in kidney transplantation, which were broadly correlated with key PCD patterns. Experimental results showed that compared to the sham group, rats in the model group had more severe tubular injury, higher Scr and BUN levels, and increased BAG3, RHOB, and MCL1 protein expression (all P<0.001).
    Conclusions These four PCD patterns are crucial in the pathogenesis of IRI in kidney transplant. MCL1, BAG3, and RHOB may serve as potential biomarkers and therapeutic targets for IRI in kidney transplantation.

     

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