Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Guangzhou Wondfo Health Science and Technology Co., Ltd, Guangzhou, China.
Front Immunol. 2024 Aug 27;15:1433393. doi: 10.3389/fimmu.2024.1433393. eCollection 2024.
Precise staging and classification of liver fibrosis are crucial for the hierarchy management of patients. The roles of lactylation are newly found in the progression of liver fibrosis. This study is committed to investigating the signature genes with histone lactylation and their connection with immune infiltration among liver fibrosis with different phenotypes.
Firstly, a total of 629 upregulated and 261 downregulated genes were screened out of 3 datasets of patients with liver fibrosis from the GEO database and functional analysis confirmed that these differentially expressed genes (DEGs) participated profoundly in fibrosis-related processes. After intersecting with previously reported lactylation-related genes, 12 DEGs related to histone lactylation were found and narrowed down to 6 core genes using R algorithms, namely S100A6, HMGN4, IFI16, LDHB, S100A4, and VIM. The core DEGs were incorporated into the Least absolute shrinkage and selection operator (LASSO) model to test their power to distinguish the fibrotic stage.
Advanced fibrosis presented a pattern of immune infiltration different from mild fibrosis, and the core DEGs were significantly correlated with immunocytes. Gene set and enrichment analysis (GSEA) results revealed that core DEGs were closely linked to immune response and chemokine signaling. Samples were classified into 3 clusters using the LASSO model, followed by gene set variation analysis (GSVA), which indicated that liver fibrosis can be divided into status featuring lipid metabolism reprogramming, immunity immersing, and intermediate of both. The regulatory networks of the core genes shared several transcription factors, and certain core DEGs also presented dysregulation in other liver fibrosis and idiopathic pulmonary fibrosis (IPF) cohorts, indicating that lactylation may exert comparable functions in various fibrotic pathology. Lastly, core DEGs also exhibited upregulation in HCC.
Lactylation extensively participates in the pathological progression and immune infiltration of fibrosis. Lactylation and related immune infiltration could be a worthy focus for the investigation of HCC developed from liver fibrosis.
准确的肝纤维化分期和分类对于患者的分层管理至关重要。乳糖化作用在肝纤维化的进展中具有新的作用。本研究致力于研究不同表型肝纤维化中具有组蛋白乳糖化特征的标志基因及其与免疫浸润的关系。
首先，从 GEO 数据库中筛选出 3 个肝纤维化患者数据集，共筛选出 629 个上调基因和 261 个下调基因，功能分析证实这些差异表达基因（DEGs）广泛参与纤维化相关过程。与先前报道的乳糖化相关基因交叉后，发现了 12 个与组蛋白乳糖化相关的 DEG，并使用 R 算法进一步缩小为 6 个核心基因，即 S100A6、HMGN4、IFI16、LDHB、S100A4 和 VIM。核心 DEG 被纳入最小绝对收缩和选择算子（LASSO）模型，以测试其区分纤维化阶段的能力。
进展性纤维化的免疫浸润模式与轻度纤维化不同，核心 DEG 与免疫细胞显著相关。基因集和富集分析（GSEA）结果表明，核心 DEG 与免疫反应和趋化因子信号密切相关。使用 LASSO 模型将样本分为 3 个簇，然后进行基因集变异分析（GSVA），结果表明肝纤维化可以分为脂质代谢重编程、免疫浸润和两者之间的中间状态。核心基因的调控网络共享几个转录因子，某些核心 DEG 在其他肝纤维化和特发性肺纤维化（IPF）队列中也表现出失调，表明乳糖化在各种纤维化病理中可能具有类似的功能。最后，核心 DEG 在 HCC 中也表现出上调。
乳糖化广泛参与纤维化的病理进展和免疫浸润。乳糖化和相关免疫浸润可能是研究由肝纤维化发展而来的 HCC 的一个有价值的焦点。
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