Work

Helixor A enhances natural killer cell activity by induction of PAI-1 expression through the p38/MAPK signaling pathway

Year: 2025

Type: article

Abstract: Helixor A, an anticancer drug, has an immunostimulatory effect that increases T and natural killer (NK) cell activity in patients with cancer and endometriosis. However, the molecular mechanisms underlying its effect on NK cells in these patients are not fully understood. In this study, we investigated the effect of helixor A on the activation and differentiation of NK cells, and elucidated the underlying mechanisms. Helixor A enhanced the cytotoxic activity of NK cells in a dose-dependent manner and simultaneously increased the expression of NK-activating receptors, particularly NKp44 and NKp30. It also increased the expression of cytolytic granules, such as granzyme B and perforin, as well as the expression of CD107a, a marker of NK cell degranulation. In addition, the production of IFN-γ and TNF-α was increased in NK cells. However, helixor A did not significantly affect the differentiation of NK cells from CD34 + hematopoietic cells. Mechanistically, helixor A activated the p38/MAPK pathway and upregulates PAI-1 expression. Inhibition of the p38 pathway abolished helixor A-induced upregulation of cytotoxic activity and PAI-1 expression in NK cells. In addition, PAI-1 overexpression in NK cells increased cytotoxicity against target cells and p38 phosphorylation. Furthermore, a PAI-1 promoter assay showed that p38 increased PAI-1 transcriptional activity. It was also confirmed that p38 interacts with PAI-1, and this interaction is increased by helixor A treatment in NK cells. Collectively, helixor A may serve as a therapeutic agent to increase NK cell cytotoxicity or transduction of PAI-1 in NK cells can be transplanted as a gene therapy. • Helixor A increases NK cell cytolytic activity. • Helixor A regulates PAI-1 expression via activation of p38/MAPK signaling pathway. • PAI-1 overexpression enhances NK cell activity and promotes p38 phosphorylation • PAI-1 interacts with p38, and helixor A increases its interaction.

Source: International Immunopharmacology

DOI: 10.1016/j.intimp.2025.115531