This review synthesizes recent evidence to dissect the non-traditional roles of protein ubiquitination in sepsis, focusing on its regulatory mechanisms in inflammatory pathway activation, such as nuclear factor kappa B (NF-κB) non-degradative signaling, in immune cell phenotypic plasticity such as macrophage M1/M2 polarization, and in organ-specific protective responses such as liver anti-oxidative stress pathways. The gene discussed is NFKB1; the disease is Sepsis.