Monocarboxylate Transporter 4 Inhibition Reduces Synovial Hyperproliferation and Metabolic Reprogramming Under Hypoxia in Rheumatoid Arthritis

作者：Mian Ma, Ting Liu, Haifeng Chen, Zhao Wang, Jie Zhou, Yu Zhou, Fenghong Yuan · 发表于：Archives of Medical Research · 年份：2025 · DOI：10.1016/j.arcmed.2025.103283 · 被引用次数：6 · 研究领域：Cancer, Hypoxia, and Metabolism、Autoimmune and Inflammatory Disorders Research、High Altitude and Hypoxia

OBJECTIVES: In hypoxic conditions, the acidic environment characteristic of rheumatoid arthritis (RA) induces metabolic changes in fibroblast-like synoviocytes (FLS), markedly promoting the synovial proliferation. Monocarboxylate transporter 4 (MCT4) plays a crucial role in cellular pH regulation and synovial fibroblast activation by regulating lactate export. This study investigates the impact of MCT4 inhibition on RA and elucidates its underlying mechanisms. METHOD: RA-FLS cells were treated with siMCT4 and VB124 (a selective MCT4 inhibitor), significantly affecting glucose and glutamine uptake and altering lactate efflux. Metabolite analysis using liquid chromatography-mass spectrometry (LC-MS) revealed the mechanisms of carbon metabolism reprogramming. ChIP-qPCR analysis demonstrated changes in hypoxia-inducible factor-1α (HIF1-α) binding to the MCT4 promoter. The therapeutic effects of siMCT4 and VB124 were validated in a collagen-induced arthritis (CIA) model, and their efficacy was assessed through arthritis scores and histological examination. RESULTS: In patients with RA, MCT4 levels are significantly elevated. Inhibition of MCT4 effectively reduces synovial hyperproliferation and impacts metabolic reprogramming. Specifically, blocking MCT4 in RA-FLS reduces glucose consumption and lactate production while remodeling the metabolic landscape by increasing fumarate, citrate, and malate levels, and decreasing glucose-6-phosphate and aspartate levels. This metabolic shif...