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 the concanavalin A-induced murine model of experimental autoimmune hepatitis (EAH), we identified proteolytic cleavage of the deubiquitinase CYLD at Asp215 as a critical molecular event that promotes disease progression. Mice harboring a macrophage-specific, cleavage-resistant CyldD215A/D215A mutation were markedly protected from hepatic injury, implicating CYLD stability as a key regulator of liver inflammation. Mechanistically, TNF-alpha-induced cleavage of CYLD in macrophages enhanced alarmin-triggered chemokine production by activating MEK1/2 signaling. Further analyses revealed that CYLD and the E3 ubiquitin ligase TRIM25 cooperatively regulate the ubiquitination status of MEK1/2 at lysine residues K192/K196. The ubiquitination of MEK1/2 promotes its activation by strengthening interaction with RAF1 and drives subsequent chemokine production. Importantly, pharmacological inhibition of MEK1/2 significantly attenuated EAH severity. Together, our study uncovers a previously unrecognized CYLD-MEK1/2 axis in macrophages that orchestrates hepatic inflammation and identifies MEK signaling as a potential therapeutic target for AIH.