Some NSAIDs dampen inflammation by switching on the activity of Nrf2.

Non-steroidal anti-inflammatory drugs, or NSAIDs, are among the most widely used drugs worldwide, available in both prescription and over-the-counter forms. NSAIDs generally work by inhibiting the activity of cyclooxygenase, a type of enzyme that drives inflammatory processes. But because the drugs often elicit off-target effects, questions remain regarding other mechanisms that might be involved in their activities. A recent study demonstrates that some NSAIDs switch on the activity of Nrf2, a type of transcription factor.

Nrf2, or nuclear factor erythroid 2-related factor 2, is a cellular protein that regulates the expression of antioxidant and stress response proteins. It is an element of the Keap1-Nrf2-ARE biological pathway. Nrf2 activates the transcription of cytoprotective proteins that protect against oxidative stress due to injury and inflammation. Sulforaphane, a compound derived from broccoli and broccoli sprouts, is the most potent naturally occurring inducer of Nrf2.

Using cells from humans and mice, the investigators determined that various NSAIDs could induce the activity of GDF15 (a type of growth factor). This induction was dependent upon the activation of Nrf2. Then, using animal models of gout (an inflammatory disorder of the joints) and endotoxemia (a systemic inflammatory condition), they observed that the NSAIDs mediated the inflammation associated with the conditions and promoted Nrf2 gene expression. Deleting the Nrf2 gene in the cells canceled out the beneficial effects of the NSAIDs on gout and endotoxemia.

This study demonstrates a novel mechanism by which NSAIDs ameliorate inflammation and answers questions regarding some of their off-target effects. It also opens the door to future research on these commonly prescribed drugs.

• View study abstract.