Announcement of Publication of a Paper Delineating the Mechanism of Removal of Aged Cells and Damaged Cells by PAI-1 Inhibitor TM5614

We are pleased to announce that the mechanism by which our PAI-1 inhibitor TM5614 removes aged cells, cancer cells, and damaged cells has been elucidated through collaborative research with Tokai University School of Medicine and Tohoku University Graduate School of Medicine, and was published in the Cell Death Discovery on March 27, 2026.

https://doi.org/10.1038/s41420-026-03076-0

Eliminating aged cells, cancer cells, and damaged cells from the body is an essential defense mechanism that protects the body and is deeply involved in the onset and progression of various diseases, including cancer, neurodegenerative diseases, arteriosclerotic diseases, and inflammatory diseases. To eliminate aged cells, cancer cells, and damaged cells, the process of “efferocytosis”¹⁾, in which macrophages phagocytose and remove dead cells, is crucial. Normally, a molecular signal called calreticulin (CRT)²⁾ appears on the surface of these dead cells, and this is recognized by the receptor on macrophages, low-density lipoprotein (LDL) receptor-related protein-1 (LRP-1), allowing the dead cells to be rapidly removed by macrophage efferocytosis. However, aged cells, cancer cells, and damaged cells also abundantly express plasminogen activator inhibitor 1 (PAI-1). Interestingly, PAI-1 and calreticulin are recognized by the same receptor LRP-1 on macrophages and compete for recognition. Because the binding affinity between PAI-1 and LRP-1 is much stronger than that between calreticulin and LRP-1, aged cells, cancer cells, and damaged cells are not removed by macrophage efferocytosis when PAI-1 molecules are present.

This paper reveals that PAI-1 competes with calreticulin, which inhibits macrophage efferocytosis and prolongs inflammation. Furthermore, the PAI-1 inhibitor TM5614 restores macrophage efferocytosis, promoting the removal of dead cells and tissue regeneration. This paper provides an important insight of elucidating part of the mechanism by which TM5614 promotes the removal of aged cells, cancer cells, and damaged cells, as well as the tissue repair and regeneration.

1) Efferocytosis: This is the process by which cells such as macrophages phagocytose and remove dead cells. It plays an essential role in promoting the resolution of inflammation, tissue repair, and maintaining homeostasis in the body.

2) Calreticulin (CRT): This protein functions as a “eat me” signal presented on the surface of dead cells. By binding to low-density lipoprotein (LDL) receptor-related protein-1 (LRP-1), a receptor on the surface of macrophages, dead cells are removed.