Cleavage‐Resistant CYLD Protects Against Autoimmune Hepatitis

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.