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

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 shift is accompanied by improvements in mitochondrial structure and function, reduced mitochondrial swelling, and decreased oxidative stress, underscoring the relationship between MCT4 inhibition and cellular energetics. Furthermore, our investigations reveal that HIF1-α directly regulates MCT4 activation, providing a molecular mechanism by which hypoxia promotes MCT4-mediated metabolic reprogramming.

Conclusion: These findings highlight MCT4 as a central regulator of RA proliferation and a promising therapeutic target.

Carbon metabolism; Fibroblast-like synoviocyte; Hypoxia; Monocarboxylate transporter 4; Rheumatoid arthritis.