The Dual Role of Natural Killer Cells in the Septic Liver

Sepsis is a life-threatening organ dysfunction caused by dysregulated host responses to infection. As an important immune organ, the liver plays a vital role in the pathophysiological process of sepsis. When sepsis occurs, the liver exhibits unique immunological characteristics, including abnormal activation of pattern recognition receptors, loss of control of the complement system, adaptive immune regulation, and hepatic Kupffer cell polarization, which together determine the outcome of septic liver. Natural killer (NK) cells are innate immune cells with different biological characteristics in the liver than circulating NK cells. Natural killer (NK) cells assume a dual role in hepatic pathophysiology, functioning as both protectors and effectors of injury. On the protective front, these cells mediate antimicrobial defense and immunomodulation through interferon-gamma (IFN-γ) secretion, maintain vascular endothelial barrier integrity via vascular endothelial growth factor (VEGF) downregulation, and regulate hepatic inflammation through the production of anti-inflammatory cytokines such as interleukin-10 (IL-10). Additionally, their cytotoxic activity effectively suppresses viral replication within the hepatic microenvironment. Conversely, NK cells contribute to hepatocellular damage through distinct deleterious mechanisms. They elaborate tumor necrosis factor-alpha (TNF-α) and IFN-γ, thereby precipitating cytokine storm formation. Through the exogenous pathway (Fas ligand/TNF-related apoptosis-inducing ligand [FasL/TRAIL]) and the endogenous pathway (perforin/granzyme), they directly induce hepatocyte apoptosis. Furthermore, NK cells regulate ferroptosis-related gene expression-including heme oxygenase-1 (Hmox1) and solute carrier family 3 member 2 (Slc3a2)-thus driving the progression of sepsis-associated liver failure. This review describes the immunological characteristics of the liver in sepsis and the mechanisms of NK protection and damage to the liver. This study provides a new perspective for exploring immunotherapy of septic liver injury in the future.