{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:29:10Z","timestamp":1787005750102,"version":"build-2736575974"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"6","license":[{"start":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:00:00Z","timestamp":1770336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,10]]},"abstract":"<jats:p>Myocarditis is a potentially fatal disease that can progress to inflammatory dilated cardiomyopathy (DCMi), a condition that is a leading cause of noncongenital heart failure in young adults. However, the mechanisms driving the transition from acute myocarditis to DCMi remain poorly understood. Although IL-17A-mediated inflammation is a well-known driver of this progression, the intracellular regulators that sustain and amplify this response remain unclear. Here, we identify the E3 ubiquitin ligase TRIM21, which is upregulated in the hearts of DCMi patients and experimental autoimmune myocarditis (EAM) mice, as a key amplifier of IL-17A-driven inflammation in cardiac fibroblasts (CFs), promoting disease progression and fibrosis. TRIM21 deficiency significantly attenuates EAM progression, reducing inflammatory cell infiltration and fibrotic remodeling. Mechanistically, TRIM21 is induced by IL-17A in CFs and promotes K27-linked polyubiquitination and lysosomal degradation of TRAF3, a negative regulator of IL-17A signaling, thereby establishing a self-reinforcing IL-17A-TRIM21\u2013TRAF3 positive feedback loop. Finally, specific knockdown of TRIM21 in CFs via the AAV9-Postn strategy effectively alleviates EAM severity. These findings identify TRIM21 as an intracellular mediator of sustained IL-17A signaling in myocarditis and highlight its potential as a therapeutic target for preventing progression to DCMi.<\/jats:p>","DOI":"10.1073\/pnas.2426265123","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T18:48:53Z","timestamp":1770403733000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["TRIM21enhances IL-17A signaling and drives autoimmune myocarditis by promoting TRAF3 lysosomaldegradation in cardiac fibroblasts"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8766-9108","authenticated-orcid":false,"given":"Yahui","family":"Song","sequence":"first","affiliation":[{"name":"Institutes of Biology and Medical Sciences, Soochow University","place":["Suzhou, China"]},{"name":"Center of Clinical Laboratory, The Fourth Affiliated Hospital of Soochow 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