{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:16:30Z","timestamp":1789992990263,"version":"4.0.1"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Inflammatory mediators are usually defined as extracellular signals, yet intracellular regulators determine which signals are converted into cell-specific, durable inflammatory programmes. Interferon regulatory factor 4 (IRF4) is a stringent test of this broader concept because its effects vary with abundance, partner choice, chromatin accessibility, metabolism, cell lineage, tissue, and disease phase. We conducted a systematised narrative review and applied a causal-discrimination framework that separates lineage determination and activation from downstream amplification, necessary mediation, sufficiency, and therapeutic tractability. Across immune compartments, IRF4 supports pathogenic T helper 17 and type 2 programmes but also maintains regulatory T cells, humoral immunity, antitumour CD8 T-cell activity, intestinal group 3 innate lymphoid cells, and skin repair. Psoriasis provides the most developed disease-linked preclinical hypothesis, although the evidence is concentrated in one 2025 study and shows pre-induction benefit in an acute mouse model rather than reversal of established human disease. Atopic dermatitis remains a candidate epithelial and immune-network context without independent target validation. Conflicting evidence on IRF4 dependence in differentiated T helper 17 cells further shows that developmental requirement cannot be assumed to predict acute therapeutic sensitivity. We therefore define IRF4 as a context-encoded intracellular mediator only when reversible, context-resolved perturbation links target engagement to a prespecified molecular programme and disease-relevant phenotype. Human-tissue perturbation, cell- and complex-resolved target engagement, lesional pharmacokinetics and pharmacodynamics, reversibility, incremental value over established pathway control, and exposure-matched safety testing are the decisive gates for translation.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1954595","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:54:49Z","timestamp":1789991689000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Interferon regulatory factor 4 as a context-dependent regulator of inflammation: transcriptional and epigenetic control, skin diseases, and translational challenges"],"prefix":"10.3389","volume":"17","author":[{"given":"Hui","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]},{"name":"Dermatological Department, Hospital of 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