Table4_Relevance of RNA N6-Methyladenosine Regulators for Pulmonary Fibrosis: Implications for Chronic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis.XLSX

N6-methyladenosine (m6A) modification plays a pivotal role in post-transcriptionally regulating gene expression and biological functions. Nonetheless, the roles of m6A modification in the regulation of chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remain unclear. Twenty-two significant m6A regulators were selected from differential gene analysis between the control and treatment groups from the GSE150910 dataset. Five candidate m6A regulators (insulin-like growth factor binding protein 2, insulin-like growth factor binding protein 3, YTH domain-containing protein 1, zinc finger CCCH domain-containing protein 13, and methyltransferase-like 3) were screened by the application of a random forest model and nomogram model to predict risks of pulmonary fibrosis. The consensus clustering method was applied to divide the treatment samples into two groups with different m6A patterns (clusters A and B) based on the 22 m6A regulators. Our study performed principal component analysis to obtain the m6A-related score of the 288 samples to quantify the two m6A patterns. The study reveals that cluster A was linked to T helper cell (Th) 2-type cytokines, while the immune infiltration of Th1 cytokines was higher in cluster B. Our results suggest that m6A cluster A is likely related to pulmonary fibrosis, indicating m6A regulators play notable roles in the occurrence of pulmonary fibrosis. The m6A patterns could be considered as biomarkers to identify CHP and IPF, which will be helpful to develop immunotherapy strategies for pulmonary fibrosis in the future.

N6-甲基腺嘌呤（N6-methyladenosine，m6A）修饰在转录后调控基因表达及生物学功能中发挥关键作用。然而，m6A修饰在慢性超敏性肺炎（chronic hypersensitivity pneumonitis，CHP）与特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）调控中的作用仍不明确。本研究从GSE150910数据集的对照组与处理组间的差异基因分析中筛选出22个核心m6A调控因子。通过随机森林模型与列线图模型预测肺纤维化风险，最终筛选得到5个候选m6A调控因子：胰岛素样生长因子结合蛋白2（insulin-like growth factor binding protein 2）、胰岛素样生长因子结合蛋白3（insulin-like growth factor binding protein 3）、YTH域包含蛋白1（YTH domain-containing protein 1）、CCCH型锌指域包含蛋白13（zinc finger CCCH domain-containing protein 13）以及甲基转移酶样3（methyltransferase-like 3）。基于上述22个m6A调控因子，本研究采用一致性聚类方法将处理组样本划分为两种不同的m6A修饰模式（聚类A与聚类B）。随后通过主成分分析（principal component analysis）对288例样本的m6A相关评分进行计算，以量化两种m6A修饰模式。研究结果显示，聚类A与辅助T细胞（T helper cell，Th）2型细胞因子密切相关，而聚类B中Th1型细胞因子的免疫浸润水平更高。本研究结果表明，m6A聚类A可能与肺纤维化发生发展相关，提示m6A调控因子在肺纤维化的发病过程中具有显著作用。m6A修饰模式可作为识别CHP与IPF的生物标志物，将为未来肺纤维化免疫治疗策略的开发提供重要参考。