UDP-glucose ceramide glucosyltransferase (UGCG) is a novel positive regulator of MyD88-driven inflammation in sepsis.

Excessive activation of MyD88 in sepsis drives uncontrolled cytokine production, leading to multi-organ injury and high mortality. However, the mechanisms that regulate MyD88 activation and link it to glycosphingolipid metabolism remain incompletely understood. Here, we identify UDP-glucose ceramide glucosyltransferase (UGCG) as a novel positive regulator of MyD88-mediated signaling and a potential biomarker for sepsis. UGCG expression was elevated in septic patients and LPS-stimulated cells. Transcriptomic analysis showed that UGCG knockdown broadly suppresses inflammatory pathways. Functionally, UGCG deficiency selectively impaired MyD88- but not TRIF-dependent signaling and reduced cytokine production. Pharmacological inhibition of UGCG using the FDA-approved drug N-butyl-deoxynojirimycin (NB-DNJ) suppressed inflammatory gene expression, immune cell infiltration, and lung injury in an LPS-induced murine sepsis model. Mechanistically, UGCG interacts with the MyD88 TIR domain to promote MyD88 protein stability, while UGCG deficiency is associated with impaired ligand-triggered MyD88 oligomerization. Together, these findings uncover a previously unrecognized UGCG-MyD88 axis that directly links UGCG to innate immune signaling independently of its enzymatic activity, and highlight UGCG as a promising therapeutic target for sepsis.