Rheumatoid arthritis from the perspective of mitophagy:interaction analysis based on multiple machine learning algorithms
- VernacularTitle:线粒体自噬视域下的类风湿关节炎:基于多机器学习算法的互作分析
- Author:
Jiagen LI
1
;
Yueping CHEN
1
;
Keqi HUANG
1
;
Shangtong CHEN
1
;
Chuanhong HUANG
1
Author Information
- Publication Type:Journal Article
- Keywords: mitophagy; rheumatoid arthritis; machine learning algorithm; weighted gene co-expression network analysis; predictive model; external validation; immune cells; biological function
- From: Chinese Journal of Tissue Engineering Research 2025;29(26):5595-5607
- CountryChina
- Language:Chinese
- Abstract: BACKGROUND:The pathogenesis of rheumatoid arthritis has not yet been fully clarified,and recent studies have shown that mitophagy is associated with rheumatoid arthritis,but the key mechanisms need to be explored in depth.OBJECTIVE:To identify and validate the core interaction genes of mitophagy in rheumatoid arthritis using multiple machine learning algorithms and to analyze its immunoregulatory process.METHODS:The rheumatoid arthritis transcriptome expression dataset GSE15573 was retrieved from the GEO database as an independent training set,with the GSE97779 and GSE55235 collections used as independent validation sets.The differentially expressed genes of rheumatoid arthritis were screened using the training set,and"WGCNA"analysis was also performed.Then we downloaded the mitophagy-related genes from the"MitoCarta3.0"database,and intersected them with the differentially expressed genes of rheumatoid arthritis and the genes in the"WGCNA"analysis module to obtain the rheumatoid arthritis-mitophagy-related genes,and then analyzed the related genes for functional enrichment to clarify the cellular pathways.Feature genes were initially identified using the"Random Forest"and"Lasso"algorithms.The overlapping genes from these two methods were further refined using the"GMM"algorithm to identify the core interaction genes between rheumatoid arthritis and mitophagy.A predictive model was then developed and validated using an external dataset.Finally,"CIBERSORT"was employed to analyze the proportions and interactions of immune cell subsets during immune infiltration,while"ssGSEA"was used to examine the associations between the rheumatoid arthritis-mitophagy core interaction genes and immune cell subsets."ssGSEA"was also utilized to analyze the"GO"and"KEGG"biological pathways of the core interaction genes.RESULTS AND CONCLUSION:(1)Totally 807 differentially expressed genes in rheumatoid arthritis were obtained by differential analysis,1 208 genes were selected from two feature modules by"WGCNA"analysis,1136 genes were sorted out from the MitoCarta 3.0 database,and 53 HUB genes were obtained from the intersection of the three genes as rheumatoid arthritis-mitophagy related genes.(2)The results of functional enrichment analysis of related genes showed that the cellular processes were mainly related to mitophagy,peroxisome metabolism,cellular senescence,and necroptosis.(3)The three machine learning algorithms identified four rheumatoid arthritis-mitophagy core interaction genes(DNAJA3,C12orf65,AKR7A2,and PDHB).The area under the curve of nomoscore was 0.989,and the area under the curve values of rheumatoid arthritis-mitophagy core interaction genes verified by the receiver operating characteristic curve of external patient samples were all greater than 0.7.(5)Immunoregulatory analysis showed that the mitophagy process in rheumatoid arthritis was closely associated with memory B cells,M0 macrophages,activated memory CD4 T cells,and resting memory CD4 T cells.(6)The biological pathway analysis revealed that the core interaction genes were strongly associated with 821"GO"pathways(|cor|＞0.8,P＜0.001)and 48"KEGG"pathways(|cor|＞0.8,P＜0.001).The key biological processes identified were related to mitochondrial DNA metabolic process,mitochondrial DNA repair,mitochondrial DNA replication,mitochondrial genome maintenance,positive regulation of mitochondrial depolarization,and positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway.To conclude,DNAJA3,C12orf65,AKR7A2,and PDHB are the core interaction genes of the mitophagy process in rheumatoid arthritis,which play key roles in disease progression by participating in specific immune processes and have precise and predictive effects on the diagnosis of rheumatoid arthritis.
