Fig. 9

The HCC microenvironment inhibits SIRT4 expression in TAMs and modulates alternative activation of TAMs, which contributes to HCC development. The HCC microenvironment inhibits SIRT4 expression in TAMs. The downregulation of SIRT4 increases FA oxidation and the expression of lipid catabolic genes, which induces alternative activation of TAMs via the FAO-PPARδ-STAT3 signalling pathway. Alternatively activated TAMs produce IL-6 to accelerate HCC development and produce IL-10 to accelerate M1 macrophage apoptosis. On the other hand, downregulation of SIRT4 in hepatocytes activates MCP-1 expression to increase TAM infiltration, which accelerates HCC development via the NF-κB signalling pathway