SIRT4 enhances the cytotoxicity of NK cells toward hepatic stellate cells and reverses liver fibrosis via AMPKα/P-p53/NKG2DL pathway

Natural killer (NK) cells exhibit antifibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cells (HSCs). SIRT4, a mitochondrial regulatory protein, plays a crucial role as a link between energy metabolism and cell viability. However, the role of SIRT4 in the cytotoxicity of NK cells toward HSCs remains unexplored. In this study, we found that SIRT4 was markedly downregulated in both mouse models and patients with LF. The loss of SIRT4 reduced the cytotoxicity of NK cells against activated HSCs, while its overexpression enhanced this cytotoxicity. Mechanistically, SIRT4 activates AMPKα to promote p53 phosphorylation and facilitates its nuclear translocation, which induces the transcription of ULBP1 and ULBP2, members of the NK group 2D Legend (NKG2DL) family of molecules. Finally, overexpression of SIRT4 activated mouse hepatic NK cells and reversed LF by constructing adeno-associated viruses (AAV) that specifically target HSCs. Thus, SIRT4 is essential for the cytotoxicity of NK cells toward HSCs, and AAV8-pGAFP-SIRT4 may serve as a therapeutic approach for managing LF. Abstract Figure