Cleavage‐Resistant CYLD Protects Against Autoimmune Hepatitis

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.