Emerging Therapeutics and Molecular Insights in Rheumatoid Arthritis

The USP5/METTL14/GLUT1 axis has emerged as a molecular pivot that links a deubiquitinase to m6A-mediated control of GLUT1 and drives glycolytic reprogramming with inflammatory activation in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS).

A new study found that USP5 stabilizes METTL14, increasing m6A modification of GLUT1 mRNA, which elevates GLUT1 expression, accelerates glycolysis, and amplifies inflammatory cytokine production. This places post‑transcriptional control of metabolism at the center of synovitis biology and suggesting metabolic targeting as a therapeutic direction for RA driven by fibroblast dysregulation.

At the molecular level, USP5 limits METTL14 ubiquitination and stabilizes the methyltransferase, increasing METTL14‑dependent m6A on GLUT1 mRNA and raising GLUT1 steady‑state levels. That change enhances GLUT1‑dependent glucose uptake and glycolytic flux in RA‑FLS, with downstream amplification of inflammatory signaling.

Functionally, USP5 or METTL14 knockdown reduced glycolysis and cytokine output, while METTL14 overexpression partially rescued USP5 loss—supporting axis specificity and highlighting multiple intervention points, including deubiquitinase inhibitors, small molecules that disrupt METTL14 function, or RNA‑targeted approaches (antisense/siRNA or nanodelivery) to lower GLUT1 mRNA m6A or expression.

In vivo, USP5 silencing reduced synovial inflammation and serum lactate in the RA rat model; in RA‑FLS it curtailed proliferation, migration, invasion, glycolysis, and cytokine release, with METTL14 overexpression yielding partial metabolic and inflammatory rescue.

This finding intersects RNA‑epitranscriptomic therapeutics and metabolic modulation in RA and complements, rather than replaces, current biologic and small‑molecule approaches that target cytokines or intracellular signaling. Post‑transcriptional targeting may offer greater cellular precision by altering pathogenic gene expression in RA‑FLS without broad systemic immunosuppression, but practical hurdles include synovial delivery, target selectivity for METTL14 or USP5, and off‑target effects on other m6A‑regulated transcripts. Long‑term modulation of ubiquitination or m6A machinery also raises safety concerns across tissues.

Key Takeaways:

• USP5 stabilizes METTL14 to increase m6A modification of GLUT1 mRNA, driving GLUT1‑dependent glycolysis and inflammatory activation in RA‑FLS.
• Targeting deubiquitination or m6A‑mediated post‑transcriptional control offers a precision‑oriented approach distinct from systemic cytokine blockade.
• Translation requires rigorous preclinical validation, synovial‑targeted delivery solutions, and early‑phase safety and pharmacodynamic endpoints to confirm on‑target metabolic modulation.