In summary, we concluded that the Acod1/ITA axis enhances the enzymatic activity of the E3 ubiquitin ligase UBR5 by alkylating the Cys2768 site, thereby promoting the K48‐linked polyubiquitination and degradation of PAD4 protein, ultimately regulating NETosis and reducing inflammation and organ damage in sepsis mice (Figure10). This evidence concerns the gene UBR5 and Sepsis.