Transglutaminase 2 regulates vimentin-dependent proteostasis during macrophage activation in sepsis

Sepsis-associated liver dysfunction (SALD) is a life-threatening condition with a high mortality rate and no mechanism-based therapy. In this study, we identified transglutaminase 2 (TG2) as a druggable driver of macrophage-mediated liver inflammation in murine lipopolysaccharide (LPS)-induced sepsis. Pharmacological inhibition of TG2 significantly improved survival and reduced multi-organ inflammation, with the liver as a primary therapeutic target. Mechanistically, TG2 activity was upregulated in macrophages, where it cross-linked vimentin to promote oligomerization and intermediate filament remodeling. Genetic ablation of TG2 or vimentin suppressed macrophage cytokine production and attenuated LPS-induced inflammation. Notably, vimentin-deficient macrophages exhibited enhanced proteasome recruitment to detergent-insoluble protein aggregates, accelerating the degradation of proinflammatory mediators such as TRAF6, thereby dampening NF-κB signaling. Proteomic profiling revealed a previously unrecognized Rab27a-positive vesicle trafficking pathway for inflammatory aggregate clearance. Together, these findings define a TG2–vimentin axis that controls macrophage activation through proteostasis regulation, linking cytoskeletal remodeling to inflammatory signaling. Our study suggests that targeting this axis, either via TG2 inhibition or modulation of vimentin-dependent proteostasis, represents a novel therapeutic strategy for the treatment of SALD.