Liver fibrosis accompanies the development of various chronic
liver diseases and promotes their progression. It is characterized by the abnormal accumulation of
extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. If
liver fibrosis is uncontrolled, it may lead to
cirrhosis and even
liver cancer, primarily
hepatocellular carcinoma (HCC). Natural killer (NK) cells are a key component of innate immunity and have miscellaneous roles in liver health and disease. Accumulating evidence shows that NK cells play dual roles in the development and progression of
liver fibrosis, including profibrotic and anti-fibrotic functions. Regulating NK cells can suppress the activation of HSCs and improve their cytotoxicity against activated HSCs or myofibroblasts to reverse
liver fibrosis. Cells such as regulatory T cells (Tregs) and molecules such as
prostaglandin E receptor 3 (EP3) can regulate the cytotoxic function of NK cells. In addition, treatments such as
alcohol dehydrogenase 3 (ADH3) inhibitors,
microRNAs, natural killer group 2, member D (NKG2D) activators, and natural products can enhance NK cell function to inhibit
liver fibrosis. In this review, we summarized the cellular and molecular factors that affect the interaction of NK cells with HSCs, as well as the treatments that regulate NK cell function against
liver fibrosis. Despite a lot of information about NK cells and their interaction with HSCs, our current knowledge is still insufficient to explain the complex crosstalk between these cells and hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, B cells, and T cells, as well as thrombocytes, regarding the development and progression of
liver fibrosis.