{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:49:13Z","timestamp":1792705753326,"version":"4.5.0"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"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:sec><jats:title>Introduction<\/jats:title><jats:p>Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by progressive fibrosis, vascular abnormalities, and immune dysregulation. Decreased expression of A20 (<jats:italic>TNFAIP3<\/jats:italic>), a key negative regulator of inflammation, has been shown to aggravate SSc pathogenesis by enhancing fibroblast activation and promoting collagen production. This study explores the therapeutic efficacy of A20 mRNA-lipid nanoparticle (LNP) delivery in restoring A20 expression and mitigating fibrosis through modulation of the TRAF6\/NF-\u03baB and Downstream Regulatory Element Antagonist Modulator (DREAM) -SMAD2 signaling pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human dermal fibroblasts were transfected with A20 mRNA -LNP and subsequently stimulated with transforming growth factor-beta (TGF-\u03b2). Protein expression levels and fibrotic markers were analyzed by Western blotting and quantitative PCR. In vivo, a bleomycin-induced mouse model of SSc received weekly intramuscular injections of A20 mRNA -LNP. The extent of fibrosis was assessed through histological analysis and immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Transfection with A20 mRNA-LNP significantly suppressed TRAF6\/NF-\u03baB signaling and reduced fibrotic marker expression <jats:italic>in vitro<\/jats:italic>. In the SSc mouse model, A20 mRNA-LNP treatment markedly attenuated skin and lung fibrosis and decreased collagen deposition. Importantly, A20 overexpression led to downregulation of DREAM <jats:italic>in vivo<\/jats:italic> and inhibition of SMAD2 phosphorylation <jats:italic>in vitro<\/jats:italic>, indicating crosstalk between inflammatory and fibrotic pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>A20 mRNA therapy effectively alleviates fibrosis by restoring A20 expression and inhibiting TRAF6\/NF-\u03baB signaling, while also downregulating DREAM, a previously unrecognized target. This dual-pathway regulation underscores the role of A20 and DREAM as central modulators of fibrotic progression. These findings highlight the potential of A20 mRNA-LNP as a novel therapeutic strategy for SSc, offering a multifaceted approach that may surpass current treatment options by simultaneously targeting interconnected pathogenic pathways.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1665998","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T05:32:23Z","timestamp":1760592743000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["A20 mRNA therapeutics ameliorate systemic sclerosis by suppressing TRAF-6\/NF-KB signaling and DREAM expression and exerting antifibrotic effects"],"prefix":"10.3389","volume":"16","author":[{"given":"A Ram","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Been","family":"Jeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye 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