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However, the pathogenic mechanisms underlying AIH remain poorly understood, limiting the development of effective therapies. Here, using a concanavalin A\u2010induced murine model of experimental autoimmune hepatitis (EAH), proteolytic cleavage of the deubiquitinase cylindromatosis (CYLD) at Asp215 is identified as a critical molecular event that promotes disease progression. Mice harboring a macrophage\u2010specific, cleavage\u2010resistant\n                    <jats:italic>\n                      Cyld\n                      <jats:sup>D215A\/D215A<\/jats:sup>\n                    <\/jats:italic>\n                    mutation are markedly protected from hepatic injury, indicating that CYLD stability is a key regulator of liver inflammation. Mechanistically, TNF\u03b1 induces CYLD cleavage in macrophages, which enhances alarmin\u2010triggered chemokine production through activation of MEK1\/2 signaling. Further analyses reveal that CYLD and the E3 ubiquitin ligase TRIM25 cooperatively regulate MEK1\/2 ubiquitination at lysine residues K192\/K196. MEK1\/2 ubiquitination promotes its activation by strengthening its interaction with RAF1 and drives subsequent chemokine production. Importantly, pharmacological inhibition of MEK1\/2 significantly attenuates EAH severity. Together, these findings uncover a previously unrecognized CYLD\u2010MEK1\/2 axis in macrophages that orchestrates hepatic inflammation and identify MEK signaling as a potential therapeutic target for AIH.\n                  <\/jats:p>","DOI":"10.1002\/advs.202513015","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T10:30:40Z","timestamp":1769596240000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cleavage\u2010Resistant CYLD Protects Against Autoimmune Hepatitis"],"prefix":"10.1002","volume":"13","author":[{"given":"Han","family":"Liu","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences  Shanghai P. R. 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences  Shanghai P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YangYang","family":"Xie","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences  Shanghai P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YangYang","family":"Wang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences  Shanghai P. R. 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