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Super\u2010enhancers (SEs) and their enhancer RNAs (eRNAs) are critical gene expression regulators and offer therapeutic potential beyond protein\u2010targeting approaches. This work hypothesizes that targeting eRNAs could reduce chronic inflammation by modulating TNF\u03b1 expression. This work generates TNF\u20109 knockout (KO) mice by deleting a Tnf\u03b1\u2010regulating enhancer region. These mice exhibit significantly reduced Tnf\u03b1 levels, improved disease outcomes, and diminished immune cell activation in models of rheumatoid arthritis (RA), psoriasis, and lipopolysaccharide (LPS)\u2010induced sepsis. Integrative epigenomic and transcriptomic analysis identify additional LPS\u2010responsive, eRNA\u2010producing enhancers as therapeutic targets. Antisense oligonucleotide (ASO)\u2010mediated knockdown of TNF\u20109 eRNA in mouse macrophages demonstrate decreased Tnf\u03b1 expression and alleviated RA symptoms. Furthermore, ASO\u2010mediated inhibition of the eRNA of the human homolog of TNF\u20109 similarly reduce TNF\u03b1 levels. These findings support eRNA\u2010targeted interventions as potential treatment for chronic inflammatory diseases.<\/jats:p>","DOI":"10.1002\/advs.202505214","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T06:05:15Z","timestamp":1753164315000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting eRNA\u2010Producing Super\u2010Enhancers Regulates TNF\u03b1 Expression and Mitigates Chronic Inflammation in Mice and Patient\u2010Derived Immune Cells"],"prefix":"10.1002","volume":"12","author":[{"given":"Minjeong","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences Graduate School of Medical Science Brain Korea 21 Project Gangnam Severance Hospital Yonsei University College of Medicine  Seoul 03722 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su 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