Cheng Zishuo, Huang Shun, Tang Qiya, Zhang Danlan, Huang Lan
Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory for Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China.
Front Genet. 2025 Jan 28;16:1505933. doi: 10.3389/fgene.2025.1505933. eCollection 2025.
Mitochondrial metabolic reprogramming in macrophages is crucial in the development and progression of inflammation. Given vitamin A's antioxidant properties and its therapeutic effects on inflammation, this study aims to elucidate how vitamin A influences mitochondrial metabolic reprogramming in inflammatory states, specifically in periodontitis, through genetic bioinformatics and experimental methods.
The study utilized the GSE16134 dataset from the Gene Expression Omnibus (GEO) database, focusing on human periodontitis. Vitamin A-targeted genes (ATGs) were identified and analyzed using CIBERSORT to explore their role in inflammation. Cluster analysis revealed two phenotypes associated with ATGs, showing differential expression of genes like , and , and immune activation patterns. Weighted Gene Co-expression Network Analysis (WGCNA) identified 145 markers correlated with ATG-guided phenotypes and inflammation. Machine learning models, combined with Gene Set Variation Analysis (GSVA), identified five key genes () linked to periodontitis. Cell Type-Specific Enrichment Analysis (CSEA) highlighted macrophages as critical in metabolic reprogramming, validated by external datasets with an AUC of 0.856 in GSE10334 and 0.750 in GSE1730678. Experimental validation showed vitamin A's role in suppressing endoplasmic reticulum stress and altering mitochondrial dynamics, as well as metabolic reprogramming influencing inflammation via the STAT3 pathway in RAW 264.7 cells.
The study identified 13 differentially expressed ATGs in periodontitis, showing strong correlations with inflammation, particularly in plasma cells, macrophages, dendritic cells, neutrophils, and mast cells. Two ATG-guided phenotypes were identified, differing in gene expression and immune activation. WGCNA and machine learning models identified 145 markers and five key genes associated with periodontitis. GSVA and CSEA analyses highlighted the JAK-STAT pathway and macrophage involvement in metabolic reprogramming. Experimental data confirmed vitamin A's effects on mitochondrial dynamics and metabolic reprogramming through the STAT3 pathway.
The study demonstrates that vitamin A's therapeutic effect on periodontitis is mediated through JAK-STAT pathway-guided mitochondrial metabolic reprogramming in macrophages. It identifies two genetic and immune-related phenotypes and five genetic identifiers associated with periodontitis risk.
巨噬细胞中的线粒体代谢重编程在炎症的发生和发展中至关重要。鉴于维生素A的抗氧化特性及其对炎症的治疗作用，本研究旨在通过基因生物信息学和实验方法阐明维生素A如何影响炎症状态下，特别是牙周炎中的线粒体代谢重编程。
本研究利用来自基因表达综合数据库（GEO）的GSE16134数据集，重点关注人类牙周炎。使用CIBERSORT识别并分析维生素A靶向基因（ATG），以探讨它们在炎症中的作用。聚类分析揭示了与ATG相关的两种表型，显示出如 、 和 等基因的差异表达以及免疫激活模式。加权基因共表达网络分析（WGCNA）确定了145个与ATG引导的表型和炎症相关的标志物。机器学习模型结合基因集变异分析（GSVA），确定了五个与牙周炎相关的关键基因（ ）。细胞类型特异性富集分析（CSEA）强调巨噬细胞在代谢重编程中起关键作用，在外部数据集中得到验证，在GSE10334中的AUC为0.856，在GSE1730678中的AUC为0.750。实验验证表明维生素A在抑制内质网应激、改变线粒体动力学以及通过RAW 264.7细胞中的STAT3途径影响炎症的代谢重编程方面发挥作用。
该研究在牙周炎中鉴定出13个差异表达的ATG，与炎症密切相关，特别是在浆细胞、巨噬细胞、树突状细胞、中性粒细胞和肥大细胞中。鉴定出两种由ATG引导的表型，在基因表达和免疫激活方面存在差异。WGCNA和机器学习模型确定了145个标志物和五个与牙周炎相关的关键基因。GSVA和CSEA分析突出了JAK-STAT途径和巨噬细胞参与代谢重编程。实验数据证实了维生素A通过STAT3途径对线粒体动力学和代谢重编程的影响。
该研究表明维生素A对牙周炎的治疗作用是通过巨噬细胞中JAK-STAT途径引导的线粒体代谢重编程介导的。它确定了两种与遗传和免疫相关的表型以及五个与牙周炎风险相关的遗传标识符。
