Cabozantinib inhibits necroptosis by targeting MLKL oligomerization and alleviates psoriasis in vivo.

Necroptosis is a regulated form of cell death characterized by inflammation, driven by activation and oligomerization of mixed lineage kinase domain-like protein (MLKL), which disrupts the plasma membrane and triggers release of damage-associated molecular patterns (DAMPs). Most current necroptosis inhibitors target upstream kinases, such as receptor-interacting protein kinase 1 (RIPK1) or RIPK3, but their limited specificity and cytotoxicity restrict therapeutic potential. Here, we report the repurposing of cabozantinib, a clinically approved multi-target tyrosine kinase inhibitor, as a novel inhibitor of necroptosis. Mechanistic studies reveal that cabozantinib acts downstream of necrosome assembly and phosphorylation events, selectively blocking MLKL oligomerization, thereby preventing necroptotic execution and DAMPs release. In an imiquimod-induced psoriasis mouse model, cabozantinib markedly reduced epidermal hyperplasia and inflammatory cytokine expression, demonstrating therapeutic efficacy in vivo. These findings establish cabozantinib as a clinically used kinase inhibitor that directly interferes with MLKL oligomerization, highlighting its potential for drug repurposing in necroptosis-driven inflammatory diseases.