Irvine, Calif., May 15, 2025 — Inflammatory diseases such as arthritis, Alzheimer’s and even certain rare genetic disorders affect millions worldwide and often have few effective treatment options. A new study from the lab of Assistant Professor Reginald McNulty at the UC Irvine Charlie Dunlop School of Biological Sciences offers hope by focusing on a promising but elusive target in the immune system: the NLRP3 inflammasome.
This protein complex plays a central role in triggering inflammation in response to infection or tissue damage. However, when it goes unchecked, it can contribute to chronic disease and damage the body instead of protecting it. Despite years of research, no drug targeting the NLRP3 inflammasome has been approved by the FDA. That’s what makes this new research — published in Trends in Pharmacological Sciences — so significant.
Professor McNulty’s lab has taken a close look at the landscape of current NLRP3-targeting drug candidates and identified where many fall short, particularly due to unwanted side effects or poor targeting. His team also made a key breakthrough: they discovered the first and only drugs to date that can bind directly to a unique part of NLRP3 called the pyrin domain.
“The NLRP3 inflammasome is a key mediator of the innate immune response to pathogen infection or tissue damage,” McNulty said. “Some humans have mutations in NLRP3 that make them more susceptible to the plethora of disorders and diseases NLRP3 is involved in, ranging from autism and arthritis to liver disease. Yet there are currently no FDA-approved drugs that target it.”
By designing molecules that resemble damaged pieces of DNA — specifically oxidized guanine — McNulty’s team was able to block NLRP3 at the pyrin domain, preventing it from kicking off the chain reaction that leads to inflammation. This novel approach could pave the way for a new generation of anti-inflammatory therapies that are more precise and safer for long-term use.
“A significant challenge is to design an NLRP3 inhibitor that doesn’t bind domains previously shown to have ill-desired off-target effects,” McNulty explained. “We showed that the pyrin domain has a similar structure to human glycosylase, and that inhibitors targeting one could be repurposed to inhibit the other.”
The implications are wide-reaching. NLRP3 activation has been linked not only to rare genetic conditions like cryopyrin-associated periodic syndrome (CAPS), but also to more common ailments like gout, heart disease, and neurodegenerative conditions such as Alzheimer’s and Parkinson’s. Targeting NLRP3 at an earlier stage in the inflammatory process could offer a more effective strategy than current treatments, which tend to block inflammation after damage has already occurred.
Looking ahead, McNulty’s lab is now using cutting-edge cryo-electron microscopy to visualize exactly how these new drug molecules bind to the NLRP3 pyrin domain. The next step would be testing their safety and efficacy in clinical trials.
“Progress in clinical trials will be key in advancing our understanding of mitigating inflammasome-based diseases,” McNulty noted.
This research underscores the critical role of basic science and federal funding in addressing some of the most urgent medical challenges of our time. As scientists continue to unravel the mechanisms behind inflammation, the discoveries made in labs like McNulty’s are bringing us closer to safer, more effective treatments that could change lives.
About the University of California, Irvine Charlie Dunlop School of Biological Sciences:
Recognized for its pioneering research and academic excellence, the Charlie Dunlop School of Biological Sciences plays a crucial role in the university’s status among the nation’s top 10 public universities, as ranked by U.S. News & World Report. It offers a broad spectrum of degree programs in the biological sciences, fostering innovation and preparing students for leadership in research, education, medicine and industry. Nestled in a globally acclaimed and economically vibrant community, the school contributes to the university’s impact as Orange County’s largest employer and a significant economic contributor. Through its commitment to exploring life’s complexities, the Dunlop School embodies the UC Irvine legacy of innovation and societal impact. For more on the Charlie Dunlop School of Biological Sciences, visit https://www.bio.uci.edu/.