Fatty acid metabolism-an emerging regulatory node in T-cell immunometabolism

While the roles of glucose metabolism and tricarboxylic acid (TCA) cycle intermediates in immune regulation are well established, the contribution of fatty acid metabolism remains less well defined. In this review, we examine current knowledge on the immunomodulatory functions of fatty acid metabolism, with a particular focus on T-cell biology. We discuss the catabolic, anabolic and signalling aspects of lipid metabolism and their influence on immune function. Short-chain fatty acids modulate T-cell epigenetics through histone acetylation, thereby impacting gene expression. Medium- and long-chain fatty acids augment fatty acid oxidation (FAO), which supports the expansion and function of regulatory T-cell populations. Very-long-chain polyunsaturated fatty acids, when cleaved from the membrane, serve as precursors for both pro-inflammatory and pro-resolving signalling molecules. Additionally, de novo fatty acid synthesis contributes to membrane biogenesis and alters acetyl-CoA availability, linking lipid metabolism to epigenetic regulation. The mechanisms described above present promising opportunities to modulate inflammation through targeted therapies. In this review, we focus on emerging targets within fatty acid metabolism pathways that show potential for influencing inflammatory responses in translational models. Specifically, we review key transcription factors, metabolic enzymes and dietary interventions, while also addressing current limitations and challenges in translating these findings to clinical settings. Although studies in murine models have yielded encouraging results, substantial gaps remain-particularly in applying these metabolic strategies to human T-cell biology. We conclude by emphasising the importance of validating these targets in ex vivo human models as a critical step towards future clinical intervention.