Understanding Efferocytosis as a Key to Fighting Cardiovascular Disease
by Amanda Chase, PhD
April 8, 2025
Billions of cells in our bodies die every day through a natural process called apoptosis, or programmed cell death. This natural process helps maintain our health. However, when these dead cells are not cleared away efficiently, they can contribute to various diseases, including cardiovascular complications like atherosclerosis.
Efferocytosis is the process by which specialized immune cells remove the dying or dead cells. This clean-up is essential for preventing inflammation and keeping tissues healthy. In diseases like atherosclerosis, where plaque builds up inside arteries, this system can fail, allowing dead cells to build up and contribute to blockages, potentially leading to heart attacks or strokes. Enhancing efferocytosis could therefore be a strategy to combat atherosclerosis and other disease resulting from dead cell and debris accumulation.
A team of researchers from Stanford and CVI members, led by first authors Yoko Kojima and Zhongde Ye and senior author Nicholas Leeper, explored whether any existing drugs had the potential to stimulate efferocytosis. In their work, published in Science Signaling, they sought to repurpose drugs that were already FDA-approved to speed up the path to clinical use.
The research team started with nearly 3,000 FDA-approved drugs in a high-throughput screen. After performing a series of analysis, they were able to identify thiothixene as a single candidate that can enhance efferocytosis.
Using a high-throughput screen of nearly 3,000 FDA-approved drugs, the researchers found that thiothixene, an antipsychotic medication approved over 50 years ago, stood out as a candidate. They found that thiothixene increased the ability of macrophages to clear away dead and dying cells, including foam cells that clog arteries in heart disease. Interestingly, the researchers found that thiothixene blocks dopamine, a neurotransmitter that was found to also inhibit efferocytosis. They also found that thiothixene triggers a pathway that increased production of Arginase 1, a molecule known to support continuous efferocytosis, or the ability of macrophages to repeatedly consume dead cells.
The work presented highlights thiothixene as a potential new therapy for promoting plaque resolution and preventing cardiovascular events. Equally exciting, it also validates drug repurposing screens as a powerful tool to identify unexpected therapeutic candidates for complex disease like atherosclerosis.
Other members of the research team, all from Stanford, include Fudi Wang, Mozhgan Lotfi, Caitlin Fox Bell, Shaunak Sanjay Adkar, Lingfeng Luo, and Changhao Fu.
Yoko Kojima, MD, PhD
Zhongde Ye, PhD
Nick Leeper, MD