METABOLIC REPROGRAMMING IN RHEUMATOID ARTHRITIS: TARGETING FATTY-ACID METABOLISM AS A THERAPEUTIC STRATEGY

Rheumatoid arthritis (RA), a chronic systemic autoimmune disorder, is estimated to affect roughly 1% of the population. Management has been transformed by conventional disease-modifying antirheumatic drugs (DMARDs), biologic agents and Janus kinase (JAK) inhibitors; however, sustained remission is still not attained by a considerable share of patients, and appreciable toxicity continues to be carried by the available options. Over the last decade, immunometabolism has been adopted as a framework through which the metabolic reprogramming of the effector cells driving synovitis, namely fibroblast-like synoviocytes (FLS), T lymphocytes, macrophages and osteoclast precursors, may be understood. What is of interest is that fatty-acid metabolism occupies a special position within that framework, since lipids are employed both as bioenergetic fuel and as precursors of pro-inflammatory and pro-resolving mediators. In the present narrative review, evidence is synthesized that lipid handling is disturbed in RA in a markedly cell-type-specific and frequently opposing fashion, and the agents acting upon uptake, de novo synthesis, desaturation, β-oxidation, thioesterase-mediated pool control, nuclear-receptor signaling, downstream lipid mediators, lipid peroxidation, sphingolipid signaling and microbiota-derived short-chain fatty acids are mapped. Candidate compounds are tabulated according to translational maturity. It is argued that translation is limited less by target discovery than by the context-dependent, tissue-divergent behaviour of these enzymes, by which the therapeutic window of systemically administered drugs is narrowed. Cell-selective delivery and disciplined repurposing are accordingly proposed as the most workable near-term strategies.

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