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Cited by 1Liver Diseases and ImmunityLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

Cleavage‐Resistant CYLD Protects Against Autoimmune Hepatitis

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Liu, Han, Su, Chen, Liu, Jianling, Xing, Mingyan, Wu, Xiaoxia, Wang, Lingxia, Zhao, Xiaoming, Zhang, Hanwen +6 more·2026·Advanced Science
DOI 10.1002/advs.202513015PMC PMC13045489
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Abstract

ABSTRACT Autoimmune hepatitis (AIH) is an immune‐mediated liver disease that can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. However, the pathogenic mechanisms underlying AIH remain poorly understood, limiting the development of effective therapies. Here, using a concanavalin A‐induced 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‐specific, cleavage‐resistant Cyld D215A/D215A mutation are markedly protected from hepatic injury, indicating that CYLD stability is a key regulator of liver inflammation. Mechanistically, TNFα induces CYLD cleavage in macrophages, which enhances alarmin‐triggered 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‐MEK1/2 axis in macrophages that orchestrates hepatic inflammation and identify MEK signaling as a potential therapeutic target for AIH.

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  • The CYLD-MEK1/2 axis represents a core mechanism of macrophage dysfunction in AIH.

    “This CYLD-MEK1/2 axis represents a core mechanism of macrophage dysfunction (41).”

    From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [41]

  • In AIH, TNF-α induces caspase-8-dependent cleavage of CYLD within macrophages, relieving its suppression of the MEK1/2-ERK signaling pathway, rendering macrophages hyperresponsive to damage signals (e.g., S100A9), leading to excessive production of neutrophil chemokines and driving liver injury.

    “In AIH, TNF-α induces caspase-8-dependent cleavage of the deubiquitinase cylindromatosis (CYLD) within macrophages, thereby relieving its suppression of the MEK1/2-ERK signaling pathway. This renders macrophages hyperresponsive to damage signals (e.g., S100A9), leading to excessive production of neutrophil chemokines and driving liver injury.”

    From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [41]

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Authors
Liu, H., Su, C., Liu, J., Xing, M., Wu, X., Wang, L., Zhao, X., Zhang, H., Xie, Y., Wang, Y., Li, H., Li, Y., Li, M., & Zhang, H.
Affiliations
  • Shanghai Institute of Nutrition and Health (CN)
  • State Key Laboratory of Protein and Plant Gene Research School of Life Sciences Peking University Beijing P. R. China
  • 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
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Li, Ming
  • Zhang, Haibing
ORCID
Venue
Advanced Science
Publisher
Wiley
Published
2026-01-28
Volume
13
Issue
19
Pages
e13015-e13015
ISSN
2198-3844 (ISSN-L)
DOI
10.1002/advs.202513015
PMC
PMC13045489
OpenAlex
W7125964242
Cited by
1
References
59
Citations by year
2026: 1
FWCI
4.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Advanced Science (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Key Research and Development Program of China (2022YFA0807300)
  • National Natural Science Foundation of China (32300630, 32270803)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
autoimmune hepatitis, CYLD, deubiquitinase, proteolytic cleavage, MEK1/2 signaling, TRIM25, macrophages, liver inflammation, chemokine production, TNF-α, Raf-1, MEK inhibition, therapeutic target
MeSH terms
Deubiquitinating Enzyme CYLD, Animals, Disease Models, Animal, Humans, Macrophages, Mice, Inbred C57BL, Hepatitis, Autoimmune, Mice, Ubiquitination

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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