Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
Gene. 2024 Dec 20;930:148840. doi: 10.1016/j.gene.2024.148840. Epub 2024 Aug 13.
Idiopathic pulmonary fibrosis (IPF) stands out as a life-threatening and one of the most severe interstitial lung diseases. The pathogenesis of IPF is not fully understood, while recent studies have highlighted the association of mitochondrial dysfunction with IPF. This study is dedicated to pinpointing crucial genes related to mitochondria that potentially impact the advancement of IPF, thereby offering new perspectives on the pathogenesis of this condition.
The Gene Expression Omnibus (GEO) database was utilized to download three datasets (GSE32537, GSE92592, and GSE150910), following which a comprehensive analysis was conducted to identify differentially expressed mitochondria-related genes (DEMTRGs) in the IPF lung tissues. Subsequently, GO and KEGG enrichment analysis of the DEMTRGs was performed. Next, external datasets and in vivo experiments were performed to validate their expression. Additionally, a Logistic regression model based on key DEMTRGs was constructed, and the model's ability to distinguish between IPF and controls was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Finally, gene set enrichment analysis (GSEA) and CIBERSORT algorithm were conducted.
We identified five key DEMTRGs (ALDH18A1, ALDH1B1, MCCC1, ACAT1, and PDHA1), ALDH18A1 and ALDH1B1 exhibited upregulated expression levels, whereas MCCC1, ACAT1, and PDHA1 showed downregulation in the lung tissue of individuals with IPF. The expression levels of these key DEMTRGs were validated by an independent external dataset (GSE53845) and the bleomycin-induced pulmonary fibrosis mice. In addition, the ROCs indicated that the diagnostic model constructed based on key DEMTRGs could effectively distinguish between IPF and controls (AUC>0.8). GSEA analysis and immune-related analysis shed light on the potential mechanisms through which these key DEMTRGs influence IPF.
Our research has pinpointed key genes associated with mitochondria that may ultimately contribute to the progression of IPF by exerting regulatory effects on mitochondrial function, thereby influencing multiple cellular processes.
特发性肺纤维化（IPF）是一种危及生命的间质性肺疾病，也是最严重的疾病之一。IPF 的发病机制尚未完全阐明，而最近的研究强调了线粒体功能障碍与 IPF 的关联。本研究旨在确定与线粒体相关的关键基因，这些基因可能影响 IPF 的进展，从而为该疾病的发病机制提供新的视角。
利用基因表达综合数据库（GEO）下载三个数据集（GSE32537、GSE92592 和 GSE150910），然后对其进行综合分析，以确定 IPF 肺组织中差异表达的线粒体相关基因（DEMTRGs）。随后，对 DEMTRGs 进行 GO 和 KEGG 富集分析。接下来，进行外部数据集和体内实验以验证其表达。此外，构建了基于关键 DEMTRGs 的 Logistic 回归模型，并通过接收者操作特征（ROC）曲线下面积（AUC）评估该模型区分 IPF 和对照的能力。最后，进行基因集富集分析（GSEA）和 CIBERSORT 算法分析。
我们确定了五个关键的 DEMTRGs（ALDH18A1、ALDH1B1、MCCC1、ACAT1 和 PDHA1），其中 ALDH18A1 和 ALDH1B1 的表达水平上调，而 MCCC1、ACAT1 和 PDHA1 在 IPF 患者的肺组织中下调。通过独立的外部数据集（GSE53845）和博来霉素诱导的肺纤维化小鼠验证了这些关键 DEMTRGs 的表达水平。此外，ROC 表明，基于关键 DEMTRGs 构建的诊断模型能够有效地区分 IPF 和对照（AUC>0.8）。GSEA 分析和免疫相关分析揭示了这些关键 DEMTRGs 影响 IPF 的潜在机制。
我们的研究确定了与线粒体相关的关键基因，这些基因可能通过对线粒体功能的调节作用最终导致 IPF 的进展，从而影响多个细胞过程。
