Abstract

Effective therapeutic targets for immune-mediated liver injury remain insufficient, necessitating the urgent development of novel therapeutic agents. Baricitinib is a selective Janus kinase (JAK) 1/2 inhibitor that shows promise in autoimmune diseases such as rheumatoid arthritis. However, its efficacy in immune-mediated liver injury has not been fully elucidated. In this study, we found that JAK2 inhibitors fedratinib and baricitinib significantly mitigated liver damage, as evidenced by reduced serum transaminase levels, diminished histopathological injury, and suppressed inflammatory responses in concanavalin A (ConA)-induced liver injury, a classic animal model of immune-mediated liver injury. Mechanistic studies revealed that baricitinib's protective effects were mediated through JAK2 inhibition in macrophages. Myeloid-specific JAK2 knockout mice exhibited blunted activation of macrophages and CD4 + T cells, conferring resistance to immune-mediated liver injury induction. In vitro, macrophages isolated from baricitinib-treated or JAK2-deficient mice displayed less mature and activated phenotypes as evidenced by lower expressions of major histocompatibility complex class II (MHC-II), inflammatory marker Ly6C, inflammatory cytokine production, and higher phagocytic capacity, which subsequently resulted in lower levels of CD4 + T cell activation. These findings collectively underscore baricitinib's therapeutic potential in modulating immune responses and restoring hepatic homeostasis in immune-mediated liver injury, positioning it as a promising therapeutic candidate for this challenging condition. Further clinical validation is warranted to translate these preclinical insights into patient care. Graphical JAK2 activity in macrophages is identified as a critical driver of immune-mediated liver injury. Genetic and pharmacological JAK2 inhibition suppresses macrophage maturation and inflammatory cytokine production while promoting M2 polarization, thereby attenuati