WASHINGTON, Aug. 18, 2025 — Acetaminophen is one of the most common painkillers and is found in hundreds of different medications. While safe at recommended doses, acetaminophen overdose is the leading cause of acute liver injury in the U.S. Now, researchers propose that a new molecule has the potential to treat acetaminophen-induced liver injury (AILI) and other inflammatory conditions. They conducted a small-scale mouse trial and found that the new compound decreased AILI-caused liver inflammation and prevented liver damage.
Jannatun Nayem Namme, a graduate student at Virginia Commonwealth University, will present her team’s results at the fall meeting of the American Chemical Society (ACS). ACS Fall 2025 is being held Aug. 17-21; it features about 9,000 presentations on a range of science topics.
Most acetaminophen overdoses are accidental, often due to people unintentionally consuming multiple products containing the painkiller or misinterpreting dosage. After taking a recommended amount of acetaminophen, a person’s liver converts a small percentage of it into a toxic molecule called N-acetyl-p-benzoquinone imine (NAPQI). Normally, the liver can quickly metabolize NAPQI into a non-toxic form. But if a person takes too much acetaminophen, NAPQI builds up and causes irreversible cell damage, leading to liver injury or death. Currently, N-acetylcysteine is the only drug available to treat AILI, and it must be administered within eight hours of overdose.
To develop novel treatments for inflammatory conditions, such as AILI, and neurodegenerative conditions, Namme and her colleagues previously focused on small molecules that reduce the activity of inflammation-causing proteins, known as inflammasomes. Inflammasomes are also involved in pyroptosis, a type of cellular death associated with AILI. While developing inflammasome inhibitors, the researchers noticed that some of the compounds they created could target a specific inflammatory protein called gasdermin D (GSDMD). GSDMD is involved in pyroptosis.
Namme and the team synthesized several different GSDMD-inhibiting compounds and tested them for their ability to bind to GSDMD. They discovered that one small molecule, which they labeled YM81, selectively binds to and inhibits GSDMD from initiating pyroptosis.
Next, the researchers treated five mice with AILI using YM81 and compared them to 10 mice given a placebo. They monitored the extent of liver damage in the animals 17 hours after the acetaminophen overdose. Compared to the placebo group, mice treated with YM81 had significantly lower levels of alanine transaminase and aspartate transaminase, two liver injury biomarkers. These results indicate that the YM81 treatment helped decrease liver inflammation by inhibiting GSDMD.
Shijun Zhang, the study’s principal investigator, says that YM81 is in the early stages of drug development. “In the future, we will focus on optimizing YM81 to increase its potency, safety and stability, in addition to exploring its therapeutic potential in additional animal models,” he says.
Namme adds that GSDMD inhibitors like YM81 have the potential to treat other inflammatory conditions. “GSDMD is a common protein involved in multiple inflammatory and neurodegenerative diseases, such as arthritis, sepsis and gout,” she says. “Targeting GSDMD could offer a therapeutic strategy to reduce the inflammation and damage from multiple diseases and causes.”
The research was partially funded by the National Institute of Aging of the U.S. National Institutes of Health.
Visit the ACS Fall 2025 program to learn more about this presentation, “Development of a novel GSDMD inhibitor for the treatment of acetaminophen-induced liver injury,” and other science presentations.
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Title
Development of a novel GSDMD inhibitor for the treatment of acetaminophen-induced liver injury
Abstract
Acetaminophen overdose can lead to severe liver injury and inflammation that plays a major role in the severity of the injury. Inflammatory proteins, such as NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) and gasdermin D (GSDMD) have been shown to play a significant role in acetaminophen-induced liver injury (AILI) and that knocking out or inhibiting these proteins can significantly relieve AILI by reducing an inflammatory form of cell death called pyroptosis in hepatocytes. GSDMD is an essential inflammatory signaling molecule that contributes to pyroptosis through oligomerization of the cleaved N-terminal fragment and the formation of a pore in the cell membrane to release intracellular contents (i.e., inflammatory cytokines such as IL-1β and IL-18). In this study, we developed YM81 as a novel scaffold of GSDMD inhibitor. YM81 is a potent inhibitor of IL-1β release through the NLRP3, NLRC4, and AIM2 inflammasomes (IC50: 950 nM). Biophysical assays also confirmed it as a direct binder of GSDMD (KD: 197.3 ± 36.28 nM). Additionally, YM81 dose-dependently inhibited GSDMD and caspase-1 cleavage in J774A.1 macrophages under LPS/nigericin stimulation. Furthermore, YM81 was also shown to alleviate AILI in mouse models, especially when compared to known inflammasome inhibitor MCC950. Taken together, this data shows that YM81 exhibits significant anti-inflammatory properties through inhibition of GSDMD and that further optimization of the scaffold could lead to even more promising therapeutics for the treatment of inflammatory disorders.