Zhang Peng, Wen Yu, Li Xin, Yang Yihong, Liang Youbang, Zhan Chenguang, Mei Liyan, Du Haifang, Chen Xiumin, Wang Maojie, Huang Runyue, Wu Xiaodong
Guangzhou University of Chinese Medicine, Guangzhou, China.
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.
Front Immunol. 2025 Jul 24;16:1611000. doi: 10.3389/fimmu.2025.1611000. eCollection 2025.
Rheumatoid arthritis (RA) is a rheumatic disease charactered by severe bone destruction. Evidence suggests that fatty acid metabolism (FAM)-related proteins can regulate inflammation of synoviocytes in RA. However, the fundamental roles of FAM regulators in RA remain to be elucidated.
We selected the GSE93272 dataset sourced from the Gene Expression Omnibus (GEO) for the classification of FAM-associated molecular subtypes and immune microenvironments in RA. Subsequently, bone marrow-derived macrophages (BMMs) with or without receptor activator of nuclear factor kappa-B ligand (RANKL) intervention were harvested for RNA sequencing (RNA-seq) to verify FAM hub gene expressions.
Difference analysis between RA samples and controls screened 53 significant FAM regulators. Random forest algorithm for RA risk prediction was utilized to identify ten diagnostic FAM regulators (hub genes). A nomogram incorporating hub genes was developed, and decision curve analysis suggested its potential utility in clinical practice. Additionally, consensus clustering analysis of these hub genes categorized RA patients to different FAM clusters (cluster A and cluster B). To quantify FAM clusters, principal component analysis (PCA) was adopted to count FAM score of every sample. ClusterB may be more linked with osteoclastogenesis in RA characterized by RXRA, IL17RA, and TBXA2R. Additionally, cases in cluster A were associated with the immunity of activated CD4 T cell, activated CD8 T cell, eosinophil, Gamma delta T cell, immature dendritic cell, MDSC, macrophage, regulatory T cell, and Type 2 T helper cell, while cluster B was linked to CD56dim natural killer cell, Natural killer T cell, T follicular helper cell, Type 1 T helper cell immunity, which has a higher FAM score. Remarkably, RNA-seq analysis confirmed the expression trend of SREBF1, FASN, CD36, SCD1 and SCD2, consistent with bioinformatics predictions.
This scoring system of FAM subtypes provided promising markers and immunotherapeutic strategies for future RA treatment.
类风湿关节炎（RA）是一种以严重骨破坏为特征的风湿性疾病。有证据表明，脂肪酸代谢（FAM）相关蛋白可调节RA中滑膜细胞的炎症。然而，FAM调节因子在RA中的基本作用仍有待阐明。
我们选择了来自基因表达综合数据库（GEO）的GSE93272数据集，用于RA中FAM相关分子亚型和免疫微环境的分类。随后，收集有或无核因子κB受体激活剂配体（RANKL）干预的骨髓来源巨噬细胞（BMM）进行RNA测序（RNA-seq），以验证FAM核心基因的表达。
RA样本与对照之间的差异分析筛选出53个显著的FAM调节因子。利用随机森林算法进行RA风险预测，以识别10个诊断性FAM调节因子（核心基因）。开发了一个包含核心基因的列线图，决策曲线分析表明其在临床实践中的潜在效用。此外，对这些核心基因的共识聚类分析将RA患者分为不同的FAM簇（A簇和B簇）。为了量化FAM簇，采用主成分分析（PCA）计算每个样本的FAM评分。B簇可能与以视黄酸X受体α（RXRA）、白细胞介素17受体A（IL17RA）和血栓素A2受体（TBXA2R）为特征的RA破骨细胞生成更相关。此外，A簇中的病例与活化的CD4 T细胞免疫、活化的CD8 T细胞免疫、嗜酸性粒细胞免疫、γδT细胞免疫、未成熟树突状细胞免疫、骨髓来源的抑制性细胞免疫、巨噬细胞免疫、调节性T细胞免疫和2型辅助性T细胞免疫相关，而B簇与CD56dim自然杀伤细胞免疫、自然杀伤T细胞免疫、滤泡辅助性T细胞免疫、1型辅助性T细胞免疫相关，其FAM评分更高。值得注意的是，RNA-seq分析证实了固醇调节元件结合转录因子1（SREBF1）、脂肪酸合酶（FASN）、脂肪酸转运蛋白CD36、硬脂酰辅酶A去饱和酶1（SCD1）和硬脂酰辅酶A去饱和酶2（SCD2）的表达趋势，与生物信息学预测一致。
这种FAM亚型评分系统为未来RA治疗提供了有前景的标志物和免疫治疗策略。
