Xin Pengfei, Pei Shaoqiang, Ma Nanshan, Xiao Lianbo
Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
The Research Institute for Joint Diseases, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China.
PeerJ. 2025 Jul 31;13:e19661. doi: 10.7717/peerj.19661. eCollection 2025.
Lactate is notably involved in the advancement of rheumatoid arthritis (RA) and osteoarthritis (OA). Nevertheless, the causal association between these conditions and lactate remains uncertain. This study aims to use Mendelian randomization (MR) to investigate their relationship with lactate and understand the genetic differences in lactate metabolism between them.
Genetic data for RA, OA, and lactate metabolism were obtained from GWAS, GEO, and MSigDB databases. MR analysis was performed using the inverse variance weighted (IVW) method. Differential gene expression analysis was conducted using the "limma" package, and Gene Set Enrichment Analysis (GSEA) was performed with GSEA software. Immune cell infiltration was assessed using the CIBERSORT platform. Validation of differentially expressed genes was carried out Western blotting. Additionally, weighted gene co-expression network analysis (WGCNA) was employed to identify hub genes, while GO and KEGG analyses were performed to compare mechanistic differences between RA and OA. experiments were conducted to assess the effects of PCK1 on lactate secretion and cellular functions in RA-FLS.
MR analysis indicated a causal relationship between RA and OA with lactate levels. Differential gene expression analysis revealed that PCK1 is a key gene underlying the metabolic differences in lactate levels between RA and OA. experiments demonstrated that knocking down PCK1 in RA-FLS affected lactate secretion, inhibited cell migration, and promoted apoptosis, suggesting its critical role in lactate metabolism. Additionally, GSEA analysis showed significant enrichment of PCK1 in the citrate cycle and gluconeogenesis signaling pathways in RA.
This study provides genetic evidence supporting the causal relationship between RA, OA, and lactate levels. Additionally, PCK1 is identified as a pivotal target implicated in the metabolic disparities of lactate between RA and OA, highlighting its potential significance in RA therapeutics.
乳酸与类风湿性关节炎（RA）和骨关节炎（OA）的进展显著相关。然而，这些疾病与乳酸之间的因果关系仍不确定。本研究旨在利用孟德尔随机化（MR）来研究它们与乳酸的关系，并了解它们之间乳酸代谢的遗传差异。
从GWAS、GEO和MSigDB数据库中获取RA、OA和乳酸代谢的遗传数据。使用逆方差加权（IVW）方法进行MR分析。使用“limma”软件包进行差异基因表达分析，并使用GSEA软件进行基因集富集分析（GSEA）。使用CIBERSORT平台评估免疫细胞浸润情况。通过蛋白质免疫印迹法对差异表达基因进行验证。此外，采用加权基因共表达网络分析（WGCNA）来识别枢纽基因，同时进行GO和KEGG分析以比较RA和OA之间的机制差异。进行实验以评估磷酸烯醇式丙酮酸羧激酶1（PCK1）对RA-成纤维样滑膜细胞（RA-FLS）中乳酸分泌和细胞功能的影响。
MR分析表明RA和OA与乳酸水平之间存在因果关系。差异基因表达分析显示PCK1是RA和OA之间乳酸水平代谢差异的关键基因。实验表明，在RA-FLS中敲低PCK1会影响乳酸分泌，抑制细胞迁移并促进细胞凋亡，表明其在乳酸代谢中起关键作用。此外，GSEA分析显示PCK1在RA的柠檬酸循环和糖异生信号通路中显著富集。
本研究提供了遗传证据支持RA、OA与乳酸水平之间的因果关系。此外，PCK被确定为与RA和OA之间乳酸代谢差异相关的关键靶点，突出了其在RA治疗中的潜在意义。
