San Antonio has one of the highest rates of metabolic dysfunction-associated steatotic liver disease (MASLD) in the United States, largely driven by high rates of obesity and diabetes in the region. This chronic liver condition can lead to serious health conditions including severe liver fibrosis or cirrhosis and liver cancer, posing a significant public health challenge. Therapy that can slow the progression of MASLD and inhibit the development of cirrhosis and liver cancer remains an urgently unmet medical need.
A study published January 31, 2025, in Nature Aging highlights a promising new drug candidate that may safely and effectively eliminate harmful cells termed senescent cells from the liver to slow the progression of MASLD and inhibit the development of cirrhosis and liver cancer. The published studies were co-led by Daohong Zhou, MD, at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and Liya Pi, PhD at The Tulane University and contributed by many other researchers from UT Health San Antonio (Yang Yang, PhD*, Araceli S. Huerta, LuZhe Sun, PhD, and Robert Hromas, MD, FACP), Tulane University (Natacha Jn-Simon*, Chunbao Sun, PhD, Tian Tian, PhD, Sreenivasulu Basha, PhD, and Xian-Ming Yin, MD, PhD), and the University of Florida (Yonghan He, PhD*, Peiyi Zhang, Wanyi Hu, Huadong Zeng, and Guangrong Zheng, PhD).
“Liver disease, particularly MASLD and hepatocellular carcinoma (HCC), disproportionately affects communities in San Antonio, where obesity and diabetes rates are high. Our study provides a promising path toward safer and more effective treatments for these diseases,” said Zhou, tenured professor of biochemistry and structural biology, associate director for drug development at the Mays Cancer Center at UT Health San Antonio and director of the Center for Innovative Drug Discovery.
Senescent cells and liver disease
Senescent cells, sometimes called “zombie cells,” are older cells that have stopped dividing but remain alive and secrete harmful toxins in the body. Accumulation of these cells has been linked to the onset and progression of MASLD, a chronic condition in which fat builds up in the liver that can lead to inflammation and damage. People with metabolic conditions like obesity and diabetes are more likely to develop MASLD.
Senolytics, a class of potential drugs designed to selectively remove senescent cells, may be an effective therapeutic for MASLD to reduce liver cancers. While senolytic therapies show promise, none are currently approved by the Federal Drug Administration for human use. This study highlights a senolytic developed in Zhou’s lab and his collaborator Zheng that proved to be safer and more effective than many of the senolytics discovered previously.
A new approach
Zhou and his collaborators developed a drug candidate that works by degrading two proteins, BCL-xl and BCL-2, that help senescent cells avoid death and promote MASLD progression. Without these proteins, senescent cells self-destruct. These proteins also promote growth and survival of some tumors and without them, cancers that rely on them are weakened and often die. The new drug candidate successfully depleted both BCL-xl and BCL-2, leading to fewer senescent cells in the liver and a decline in MASLD progression and liver cancer development, all while avoiding toxic side effects of previous senolytics targeting these proteins.
Testing in liver disease model
Testing the drug candidate in cell culture and in a mouse model for MASLD developed by Pi demonstrated that it was a more powerful senolytic than predecessors and was able to target senescent cells more selectively in the liver. Notably, by targeting senescent liver cells it reduced fat buildup in the liver and scar tissue formation due to liver damage in the mouse model.
Potential to inhibit liver cancer
Hepatocellular carcinoma is the most common form of liver cancer with about 42,000 people diagnosed each year in the United States, according to the American Cancer Society. The study found that this novel drug candidate reduced the number and size of liver tumors in mice with MASLD, suggesting it could help inhibit liver cancer development. Importantly, they showed that the treatment was effective in mice even after the mice developed substantial MASLD and liver fibrosis but before cancer had fully developed via reducing senescent cell accumulation. Unfortunately, once cancer was established, the drug candidate did not stop tumor progression unless it was a BCL-xl/BCL-2-dependent tumor.
Advantages over existing treatments
Unlike broad-spectrum senolytics, which indiscriminately kill senescent cells (some of which may be beneficial for tissue repair), this new senolytic can selectively clear harmful senescent cells harming an organ, such as those in the liver. This selectivity is important, as indiscriminate removal of all senescent cells could disrupt wound healing and organ function, especially in older individuals.
Zhou said this senolytic’s ability to selectively clear harmful senescent liver cells with reduced toxicity to platelets suggests it may offer a safer and more effective alternative to other senolytic therapies for MASLD.
“This breakthrough in targeted senolytic therapy opens the door to developing even more selective and less toxic drugs. Moving forward, we aim to refine these treatments to tackle a wider range of liver diseases and potentially other age-related conditions, ensuring broader clinical impact,” said Zhou.
*Co-first authors