CXCR3+ LEF1low NK cells cause immunopathological hepatic damage in MASH

Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is a systemic metabolic disorder associated with obesity that leads to liver disease (such as hepatocyte damage and fibrosis) and hepatocellular carcinoma. During the progression of MASH, the accumulation of metabolites triggers hepatocyte damage and inflammation. however, the mechanisms underlying MASH-related hepatic damage remain incompletely understood. Using several mouse models that simulate critical features of human MASH (hereinafter referred to as MASH mice) and single-cell transcriptomics sequencing, we identify a distinct NK cell subset critically implicated in hepatic immunopathology. We found NK cells with tissue residency characteristics (IL21R, RGS1) and effector functions (GZMK) aggregated in the livers of MASH mice. These CXCR3+ NK cells exhibited reduced activity of the LEF1 transcription factor and were found with elevated abundance in the context of MASH, as observed in both experimental mice and human subjects. The mechanism involves IL-21 sensitizes the responsiveness of hepatic CXCR3⁺ NK cells to metabolic stimuli, such as Acetate and CXCL9, by downregulating LEF1 and upregulating CXCR3, collectively triggering immunopathological hepatic damage. Hepatic CXCR3+LEF1low NK cells from MASH patients and mice exhibit similar transcriptional profiles. During MASH progression, CXCR3+ LEF1lowNK cells were recruited to and retained in the liver, were metabolically reprogrammed in the hepatic microenvironment, and mediated MHC class I-independent auto-destructive killing of hepatocytes. CXCR3+LEF1lowNK cell cytotoxicity fundamentally diverges from canonical anti-tumor NK cell immunity, mechanistically distinguishing auto-destructive versus protective NK cell functional modalities.