Acod1 Promotes PAD4 Ubiquitination via UBR5 Alkylation to Modulate NETosis and Exert Protective Effects in Sepsis

Neutrophil extracellular traps (NETs) are reticular structures released by neutrophils, and the process of their formation is called NETosis. NETs play a key role in the pathological process of sepsis. However, the specific regulatory mechanism has not been fully clarified. This study finds that the levels of NETs in peripheral blood are significantly elevated in clinical sepsis patients and cecal ligation and puncture (CLP) mouse models, and the expression of Acod1 is closely related to the generation of NETs. Acod1 knockout led to a further increase in NETs levels in CLP mice, aggravated the inflammatory response, worsened organ damage, and reduced the survival rate. Further studies indicate that E3 ubiquitin ligase UBR5 interacts with PAD4 (one of the core proteins for NETs generation). Acod1/itaconate (ITA) enhanced the enzymatic activity of UBR5 through alkylation modification, promoting the K48-linked polyubiquitination and degradation of PAD4, thereby inhibiting NETosis. In conclusion, this study combines transcriptomics, metabolomics, genetic engineering, and co-immunoprecipitation techniques to reveal the molecular mechanism of Acod1/ITA in regulating NETs, providing new potential targets and theoretical basis for the treatment of sepsis.