Lin Qiumei, Chen Junxian, Zhou Lingling, Fang Min, Wei Caibiao, Huang Taijun, Xu Yulong, Gao Jie, Liu Fengfei, Tang Zeli, Zhu Jian-Kang, Yang Weilong
Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, China.
Engineering Research Center for Tissue & Organ Injury and Repair Medicine, Guangxi Medical University Cancer Hospital, Nanning, China.
Parasit Vectors. 2025 Jul 27;18(1):301. doi: 10.1186/s13071-025-06947-0.
Although recent research has highlighted lactylation, a post-translational modification driven by elevated lactate levels, as a critical regulator of key cellular pathways in hepatocellular carcinoma (HCC), its contribution to the poor prognosis of Clonorchis sinensis (Cs)-infected HCC remains poorly understood.
We first identified the significant upregulation of the lactate metabolism enzyme LDH in Cs-infected HCC patients through clinical retrospective analysis. We then conducted a multi-omics analysis (RNA-Seq, ATAC-Seq, WGBS-Seq, oxWGBS-Seq, and ChIP-Seq) to examine the differences in 392 lactate metabolism-related genes (LMRGs) between Cs-infected and Cs-noninfected HCC tumors. Six key differentially expressed LMRGs were further validated using RT-qPCR assays to confirm their expression and potential role in HCC progression.
The differential expression levels of 8 LMRGs, along with 71 accessible regions and 42 CpG sites in the promoters of LMRGs, were identified. Notably, we also demonstrated that histone modifications, including H3K9ac, H3K79me2, H3K4me2, H3K4me3, H3K27ac, and H3K4me1, were associated with chromatin accessibility in the promoters of LMRGs. Finally, the TCGA-LIHC cohort confirmed that the differential expression of LMRGs between Cs-infected and Cs-noninfected HCC tumors significantly affects the survival outcomes of HCC.
Our findings revealed that lactylation plays an important role in reshaping the characteristics of HCC during Cs infection, expanding our understanding of the unique features of Cs-infected HCC.
尽管最近的研究强调了乳酸化（一种由乳酸水平升高驱动的翻译后修饰）是肝细胞癌（HCC）关键细胞通路的关键调节因子，但其对华支睾吸虫（Cs）感染的HCC预后不良的影响仍知之甚少。
我们首先通过临床回顾性分析确定了Cs感染的HCC患者中乳酸代谢酶LDH的显著上调。然后，我们进行了多组学分析（RNA测序、ATAC测序、全基因组亚硫酸氢盐测序、氧化全基因组亚硫酸氢盐测序和染色质免疫沉淀测序），以检查Cs感染和未感染Cs的HCC肿瘤之间392个乳酸代谢相关基因（LMRGs）的差异。使用RT-qPCR分析进一步验证了六个关键差异表达的LMRGs，以确认它们在HCC进展中的表达和潜在作用。
确定了8个LMRGs的差异表达水平，以及LMRGs启动子中的71个可及区域和42个CpG位点。值得注意的是，我们还证明了组蛋白修饰，包括H3K9ac、H3K79me2、H3K4me2、H3K4me3、H3K27ac和H3K4me1，与LMRGs启动子中的染色质可及性相关。最后，TCGA-LIHC队列证实，Cs感染和未感染Cs的HCC肿瘤之间LMRGs的差异表达显著影响HCC的生存结果。
我们的研究结果表明，乳酸化在Cs感染期间重塑HCC特征方面发挥着重要作用，扩展了我们对Cs感染的HCC独特特征的理解。
