{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:30:37Z","timestamp":1788298237669,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Mitochondrial dysfunction is implicated in the pathogenesis of primary biliary cholangitis (PBC), but the roles of mitochondria-related genes (MRGs) remain unclear. We aimed to identify key MRGs associated with PBC and validate their expression at transcriptional and protein levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Peripheral blood from PBC patients and healthy controls underwent RNA-seq. MRGs were sourced from MitoCarta 3.0. After quality control, differentially expressed genes were defined between PBC and controls and integrated with weighted gene co -expression network analysis to obtain candidate genes. LASSO and SVM-RFE selected hub genes, whose diagnostic performance was assessed by ROC in both the discovery cohort and an external\u00a0validation dataset. Functional enrichment, immune-cell composition analyses, and regulatory network construction (miRNA\/lncRNA\/TF) were performed. Protein and mRNA expression were validated by liver -tissue immunohistochemistry and peripheral-blood RT-qPCR, respectively. Disease correlation and drug-prediction analyses were conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SHANK2 and TGM2 were identified as hub MRGs, showed higher expression in PBC, and achieved AUC values &amp;gt;0.7. Enrichment linked SHANK2 to Bcell receptor, T-cell receptor, and Wnt signaling pathways, while TGM2 associated with oxidative phosphorylation and nucleotide metabolism. Immune-cell profiles differed between PBC and controls, and selected cell types correlated with hub-gene expression. Regulatory analyses suggested modulation of SHANK2 and TGM2 by molecules including SLFN12L and DNAH10OS. Immunohistochemistry revealed elevated, stage-associated protein expression of both genes in PBC liver tissues, and RT-qPCR confirmed higher peripheralblood mRNA levels. Drug\/disease analyses indicated therapeutic potential for targeting these genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>SHANK2 and TGM2 emerge as key MRGs linking mitochondrial dysfunction with immune dysregulation in PBC and may serve as diagnostic biomarkers and therapeutic targets; further mechanistic and clinical validation is warranted.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1644682","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T05:26:49Z","timestamp":1759987609000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The role of mitochondria-related key genes in primary biliary cholangitis was analyzed based on transcriptome sequencing 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