Fidarestat Induces Glycolysis of NK Cells through Decreasing AKR1B10 Expression to Inhibit Hepatocellular Carcinoma

Abstract The aldose reductase inhibitor Fidarestat has been noted to have efficacy in treating a variety of tumors. To define its role in hepatocellular carcinoma (HCC), we induced a HCC xenograft model in mice, which were treated with different doses of Fidarestat. The amount of natural killer (NK) cells and related inflammatory factors were detected in the serum of the mice. Fidarestat inhibited HCC tumor growth and lung metastasis in vivo and increased NK cell number, as well as levels of NK cell-related inflammatory factors in mouse serum. NK cells were then co-cultured with the HCC cell line in vitro to detect effects on HCC cell progression after Fidarestat administration. The glycolysis activity of the NK cells was evaluated by extracellular acidification rate, while AKR1B10 expression was detected by Western blot analysis. Administration of Fidarestat down-regulated the expression of AKR1B10 in NK cells and promoted NK cell glycolysis to enhance their killing activity against HCC cells. However, depletion of NK cells or upregulation of AKR1B10 attenuated the anticancer activity of Fidarestat. Taken together Fidarestat down-regulated AKR1B10 expression in NK cells to promote NK cell glycolysis, thereby alleviating HCC progression.