Metabolic pathways → chromatin effects → immune fate outcomes.
| Pathway | Key metabolite | Chromatin effect | Immune fate effect | Disease context | References |
|---|---|---|---|---|---|
| Glycolysis | Lactate, pyruvate | Increased H3K27ac via acetyl-CoA availability; HIF-1α-driven enhancer activation | Promotes Th17 differentiation, effector T-cell expansion, inflammatory macrophages, and invasive FLS | RA synovium shows high glycolytic flux; Th17-FLS inflammatory loops | [173–175] |
| Oxidative phosphorylation (OXPHOS) | NAD+, ATP | Sirtuin-dependent histone deacetylation; repression of effector loci; maintenance of FOXP3 enhancer integrity | Supports Tregs, Bregs, tolerogenic DCs, and M2 macrophages | NAD+ depletion in RA/SLE reduces Treg stability and mitochondrial fitness | [176–178] |
| Fatty-acid oxidation (FAO) | Acetyl-CoA, NADH | Promotes SIRT1/3 activity; enhances repressive chromatin landscapes | Stabilizes Treg phenotype; supports long-lived regulatory programs | FAO impairment contributes to Treg instability in autoimmunity | [56, 178, 179] |
| Glutaminolysis | α-Ketoglutarate (αKG) | αKG supports TET-mediated DNA/histone demethylation; maintains open chromatin at regulatory genes | Enables Treg and Breg epigenetic stability; excessive glutaminolysis drives effector expansion | High glutamine flux in RA FLS; αKG dysregulation affects Treg tolerance | [60, 180, 181] |
| One-carbon metabolism | SAM, SAH | SAM availability regulates DNA/histone methylation; SAM depletion causes global hypomethylation | Controls FOXP3 methylation status; impacts lineage fidelity | SAM: SAH imbalance seen in RA and SLE; influences T-cell differentiation | [182, 183] |
| Redox/ROS regulation | ROS, NAD+/NADH | ROS oxidizes 5mC → 5hmC; alters methylation fidelity; NAD+ levels dictate sirtuin activity | High ROS favors inflammatory programs; balanced redox supports regulatory phenotypes | Excess ROS in RA/SLE fuels inflammatory memory in T cells and macrophages | [184–186] |
| TCA cycle dysfunction | Succinate, fumarate | Succinate/fumarate inhibit αKG-dependent demethylases → hyperacetylated, pro-inflammatory chromatin | Enhances IL-1β, TNF expression, and effector persistence | Elevated succinate in RA macrophages drives pathologic cytokine output | [43, 187] |
| Mitochondrial integrity & mitophagy | NAD+ | Healthy mitochondria support epigenetic precision; dysfunctional mitochondria increase ROS & chromatin noise | Supports Treg stability and prevents exhaustion; dysfunction drives inflammatory cell fate | Mitochondrial fragmentation in FLS and T cells reinforces chronic inflammation | [188–190] |
ATP: adenosine triphosphate; Breg: regulatory B cell; FLS: fibroblast-like synoviocytes; FOXP3: forkhead box P3; HIF-1α: hypoxia-inducible factor-1 alpha; IL-1β: interleukin-1 beta; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator-1 alpha; RA: rheumatoid arthritis; ROS: reactive oxygen species; SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine; SIRT1/3: sirtuin 1/3; SLE: systemic lupus erythematosus; TCA: tricarboxylic acid; TET: ten-eleven translocation; TNF: tumor necrosis factor; Treg: regulatory T cell; 5mC: 5-methylcytosine; 5hmC: 5-hydroxymethylcytosine.
OAA: Conceptualization, Investigation, Visualization, Writing—original draft. MMN: Conceptualization, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing. Both authors read and approved the submitted version.
The authors declare no conflict of interest.
Not applicable.
Not applicable.
Not applicable.
Not applicable.
Not applicable.
© The Author(s) 2026.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.