<p>Immune cells can rewire their metabolism in response to various stimuli. Crosstalk between the nucleus and mitochondria allows for tight regulation of this metabolic reprogramming. Research has emerged showing several TCA cycle-derived metabolites exhibiting moonlighting functions in the nucleus, modulating chromatin modifications in order to control inflammation. These TCA cycle-derived metabolites include acetyl-CoA, α-ketoglutarate, succinate, fumarate, itaconate, and succinyl-CoA which can modify DNA or histone to drive or inhibit gene expression. In this review, we look at the mechanisms of TCA cycle metabolites’ non-canonical functions in the nucleus in the context of inflammation. In addition, we discuss the known and possible links between these metabolites’ nuclear moonlighting functions and the pathogenesis of diseases, including inflammatory diseases and cancers.</p>