Yale Study Discovers New Mode of Action by Certain NSAIDs

Research out of Yale University reports a previously unknown process by which some non-steroidal anti-inflammatory drugs (NSAIDs) affect the body—findings that may explain why similar NSAIDs produce different clinical outcomes and could inform how they are used in the future.

NSAIDs are used to treat pain and inflammation and include common household medications like ibuprofen and aspirin. Despite belonging to the same category, different NSAIDs can have unexpected and unexplained effects on many diseases, including heart disease and cancer. For example, some NSAIDs prevent heart disease while others cause it, some NSAIDs have been linked to decreased incidence of colorectal cancer, and different NSAIDs have a wide range of effects on asthma. These varying effects can occur even at low doses.

Also, the anti-inflammatory effects of NSAIDs were, until now, believed to arise solely through the inhibition of certain enzymes. But this mechanism does not account for many clinical outcomes that vary across the family of drugs. 

A Yale study published recently in the journal Immunity may have discovered the true cause of these variations. Using cell cultures and mice, the team uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. They found that only some NSAIDs—including indomethacin, which is used to treat arthritis and gout, and ibuprofen—activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2. Among its many actions, NRF2 triggers anti-inflammatory processes in the body.

“It’s interesting and exciting that NSAIDs have a different mode of action than what was known previously,” says Anna Eisenstein, an instructor at the Yale School of Medicine and lead author of the study. “And because people use NSAIDs so frequently, it’s important we know what they’re doing in the body.”

The research team can’t say for sure that NSAIDs’ unexpected effects are due to NRF2 without further research, but Eisenstein says the fundings “are suggestive.” She is now looking into some of the drugs’ dermatological effects—causing rashes, exacerbating hives, and worsening allergies—and whether they are mediated by NRF2.

The discovery also needs to be confirmed in humans. But if it is, the findings could have impacts on how inflammation is treated and how NSAIDs are used. Several clinical trials are already evaluating whether NRF2-activating drugs are effective in treating inflammatory diseases like Alzheimer’s disease, asthma, and various cancers; this research could inform the potential and limitations of those drugs. Additionally, NSAIDs might be more effectively prescribed going forward, with NRF2-activating NSAIDs and non-NRF2-activating NSAIDs applied to the diseases they’re most likely to treat.

The findings may also point to entirely new applications for NSAIDs, said Eisenstein, since NRF2 controls a large number of genes involved in a wide range of processes—including metabolism, immune response, and inflammation. The protein has also been implicated in aging, longevity, and cellular stress reduction. “That NRF2 does so much suggests that NSAIDs might have other effects, whether beneficial or adverse, that we haven’t yet looked for,” adds Eisenstein.