Immunometabolic control of cytokine production by micronutrients in health, aging, and inflammation.

Micronutrients serve as critical metabolic sensors and epigenetic regulators that orchestrate cytokine production through multiple overlapping signalling cascades, transcriptional networks, and cellular metabolic states. This comprehensive review synthesizes recent research demonstrating that micronutrient status regulates cytokine biology at five hierarchical levels: (i) nutrient sensing via mTORC1/GCN2 and amino acid sensor networks; (ii) transcriptional control through VDR/RARα-mediated epigenetic remodelling and histone deacetylase inhibition; (iii) redox signalling via SELENOK/selenoprotein-stabilized calcium homeostasis and Nrf2/ARE pathway activation; (iv) Pyroptosis/ferroptosis execution via metallothionein-zinc-caspase axes and NLRP3/GSDMD regulation; and (v) metabolic bioenergetics through NAD+/CD38/SIRT-mediated immune cell differentiation and aging. Recent discoveries establish that vitamin D directly suppresses IL-22 through repressive VDREs independent aryl-hydrocarbon receptor (AhR) signalling, zinc-metallothionein-3 that suppresses non-canonical inflammasome activation via TRIF-IRF3-STAT1 modulation, selenium-dependent SELENOK which stabilizes IP3 receptor-mediated store-operated calcium entry in immune cells, and folate-dependent one-carbon metabolism generating S-adenosyl methionine (SAM) that tunes epigenetic landscapes of cytokine genes. This review compiles the integrated mechanistic frameworks linking micronutrient availability to immunometabolic checkpoints, with implications for nutritional immunotherapy in chronic inflammatory diseases and immune-senescence.