Background & aims: Hepatic immune microenvironment plays a pivotal role in the development of nonalcoholic steatohepatitis (NASH). However, the role of natural killer (NK) cells, accounting for 10%-20% of liver lymphocytes, in NASH is still unclear. In this study, we aim to investigate the functional significance of NK cells in NASH evolution. Methods: NASH was induced in mice fed methionine- and choline-deficient diet (MCD), choline-deficient high-fat diet (CD-HFD), or high-fat diet with streptozotocin injection (STAM model). NK cell deficient mice (Nfil3-/-) and neutralization antibody (PK136) were used in this study. Results: Activated liver NK cells were identified with increased expression of NKG2D, CD107a, and interferon-γ but decreased inhibitory NKG2A. With NK cell deficiency Nfil3-/- mice, the absence of NK cells ameliorated both MCD- and CDHF- induced NASH development with significantly decreased hepatic triglycerides, peroxides, alanine aminotransferase, and aspartate aminotransferase compared with Nfil3+/+ mice. Further molecular analysis unveiled suppressed pro-inflammatory cytokines and associated signaling. Mechanistically, NK cells isolated from NASH liver secreted higher levels of pro-inflammatory cytokines (interferon-γ, interleukin 1β, interleukin 12, CCL4, CCL5, and granulocyte-macrophage colony-stimulating factor), which could activate hepatic JAK-STAT1/3 and nuclear factor kappa B signaling and induce hepatocyte damage evidenced by elevated reactive oxygen species and apoptosis rate. Moreover, neutralization antibody PK136-dependent NK cell depletion can significantly alleviate MCD-induced steatohepatitis with suppressed cytokine levels and JAK-STAT1/3 activity. Conclusions: NK cells in NASH liver are activated with a more pro-inflammatory cytokine milieu and promote NASH development via cytokine-JAK-STAT1/3 axis. Modulation of NK cells provides a potential therapeutic strategy for NASH.Keywords: Cytokine; JAK/STAT; Natural Killer Cell; Nonalcoholic Steatohepatitis.

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乐备实（上海优宁维生物科技股份有限公司旗下全资子公司），是国内专注于提供高质量蛋白检测以及组学分析服务的实验服务专家，自2018年成立以来，乐备实不断寻求突破，公司的服务技术平台已扩展到单细胞测序、空间多组学、流式检测、超敏电化学发光、Luminex多因子检测、抗体芯片、PCR Array、ELISA、Elispot、PLA蛋白互作、多色免疫组化、DSP空间多组学等30多个，建立起了一套涵盖基因、蛋白、细胞以及组织水平实验的完整检测体系。

 
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