Scientists have developed a drug that hunts down harmful “zombie cells” in the liver, bringing new hope to millions of diseases with fatty liver disease.
The experimental compound, known as 753b, selectively destroys senescent cells that have stopped dividing but refuse to die, instead extracting inflammatory toxins that damage the tissue around the tissue.
The study, published in Natural Aging, demonstrates how this targeted approach prevents metabolic dysfunction-related steatogenic liver disease (MASLD) from advancing to more severe conditions. MASLD affects 38% of adults worldwide, representing one of the fastest causes of liver-related deaths, especially in obesity and diabetes.
Precise blow to cellular troublemakers
Unlike previous nasal solution drugs that clear senescent cells throughout the body, 753B is specifically concentrated in the liver and spleen. This method of tissue selection comes from an unexpected discovery in pharmacokinetic studies – this compound naturally accumulates in these organs, resulting in higher concentrations that last longer.
“This is the first study that shows that this compound has a very high efficiency compound,” said Liya Pi, assistant professor of pathology at Tulane University’s School of Medicine and corresponding author of the study. The drug is by degrading the effects of two survival proteins Bcl-XL and Bcl-2, that is, senescent cells rely on avoiding natural cell death.
In laboratory tests, 753B is about 14 times more potent than ABT263, a well-known plug-soluble substance that can cause dangerous platelet drops. The new compounds exhibit minimal platelet toxicity while maintaining superior efficiency for senescent cells of different tissue types.
From fatty liver to cancer prevention
The team tested 753B in Stam mice, a built-in model that mimics human progression from simple fat accumulation to inflammation, scars, and ultimately liver cancer. These mice developed the entire disease with a penetration rate of 100%, which is ideal for studying intervention strategies.
Treatment outcomes vary depending on time. When researchers managed 753B during the transition period from inflammation to early cancer development (equivalent to treating humans but not end-stage disease), the drug effectively reduced:
- Compared with untreated mice
- Scar tissue formation and inflammation markers
- Number and volume of tumors in animals with cancer prone to cancer
- Liver enzyme levels indicate cell damage
However, early treatment during initial fat accumulation has no benefit and late treatment after tumor establishment has proven ineffective. This timing-dependent response suggests that the drug works by preventing disease progression rather than reversing identified damage.
Targeting the roots of liver damage
Studies have shown that senescent cells accumulate mainly in surrounding hepatocytes, i.e., near the entry point of blood vessels, and appear to be most susceptible to metabolic stress. These zombie cells express high levels of aging markers and inflammatory factors that drive disease progression.
“Chronic fatty liver disease is a global problem,” PI explained. “The drug not only selectively targets senescent cells and slows down the progression of MASLD, but also stops the development of associated liver diseases as well as hepatocellular carcinoma.”
Hepatocellular carcinoma is the most common form of liver cancer, and as obesity rates rise worldwide, cases associated with MASLD have increased rapidly. Currently, there is only one FDA-approved drug to treat the inflammatory stage of fatty liver disease, which makes the widespread protective effect of 753b particularly noteworthy.
By selective security
One issue with nasal soluble therapy involves the potential of eliminating beneficial senescent cells that help wound heal and tissue maintenance. The liver-specific accumulation of 753b can solve this problem by senescent cells in other organs that may have protective functions.
The selectivity of the drug exceeds the tissue distribution. Laboratory studies have confirmed that 753b cannot kill certain types of senescent cells, such as preadipocytes, that are not dependent on Bcl-XL and BCl-2. This built-in selectivity can reduce unintended consequences compared to the wider nasal congestion approach.
Safety assessment in elderly mice showed that platelet counts of 753b were reduced to normal levels without causing severe drops associated with similar compounds. The treated animals remained stable in weight and did not have significant pathological changes during treatment.
The study represents a collaboration between Tulane University, the University of San Antonio Health Science Center, and the University of Florida. While promising, PI stressed, “More research is needed, but hopefully this is a potential tool that patients can use to control the disease one day.”
As MASLD cases are expected to surge along with global obesity trends, nasal solution therapies such as 753B can provide new strategies to prevent irreversible damage before it occurs.
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