Disease-specific roles of epigenetic and metabolic therapeutics in autoimmune rheumatology.
| Disease | Dominant pathogenic axis | Most relevant therapeutic approaches | Rationale for therapeutic relevance | Key translational considerations |
|---|---|---|---|---|
| RA | Stroma-immune coupling; Th17/Treg imbalance; FLS inflammatory memory | AMPK activators, BET inhibitors, EZH2 inhibitors, nanoparticle-targeted stromal delivery, CAR-Tregs/tolDCs | Target synovial glycolysis, stromal epigenetic imprinting, and effector-regulatory imbalance | Synovial penetration, chronic-use safety, biomarker-guided patient selection |
| SLE | Interferon-driven immune activation; B-cell and pDC dysfunction | mTOR inhibitors, NAD+-targeting strategies, HDAC inhibitors, EZH2 inhibitors, B-cell-directed metabolic modulation | Target interferon-associated chromatin activation, B-cell metabolic rewiring, and systemic immune instability | Heterogeneous disease activity, systemic toxicity risk, stratification by interferon/metabolic signatures |
| Sjögren’s syndrome | Epithelial-immune crosstalk; glandular inflammatory activation | Metabolic modulators targeting epithelial stress, epigenetic modulators, B-cell/tolDC-based strategies | Target epithelial glycolytic activation, interferon-responsive chromatin states, and local ectopic immune activation | Limited tissue-specific delivery options, fewer disease-specific trials, need for gland-focused biomarkers |
| SSc | Fibroblast-driven fibrosis; profibrotic chromatin lock-in | PPAR-γ agonists, AMPK activators, antifibrotic metabolic modulators, EZH2/epigenetic targeting, targeted delivery platforms | Target fibroblast glycolytic-fibrotic reprogramming and stable profibrotic epigenetic states | Need for early intervention, fibrosis reversibility limits, and long-term safety in chronic disease |
AMPK: AMP-activated protein kinase; BET: bromodomain and extra-terminal; CAR-Tregs: chimeric antigen receptor regulatory T cells; EZH2: enhancer of zeste homolog 2; FLS: fibroblast-like synoviocytes; HDAC: histone deacetylase; mTOR: mechanistic target of rapamycin; pDC: plasmacytoid dendritic cell; PPAR-γ: peroxisome proliferator-activated receptor gamma; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; SSc: systemic sclerosis; tolDCs: tolerogenic dendritic cells.
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.
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