Dexketoprofen enhances NLRP3 activation via ATPase activity after canonical stimuli

TL;DR

Dexketoprofen, an anti-inflammatory drug, unexpectedly boosts NLRP3 inflammasome activity in macrophages, increasing inflammation.

Contribution

This study is the first to show that dexketoprofen enhances NLRP3 activation via ATPase activity in human macrophages.

Findings

Dexketoprofen increases IL-1β release and cell death in macrophages after canonical NLRP3 stimuli.

Dexketoprofen binds to the NLRP3 NATCH domain and promotes ATP hydrolysis, facilitating NLRP3 activation.

The NLRP3 inhibitor MCC950 reduces the pro-inflammatory effects of dexketoprofen.

Abstract

Inflammasomes are crucial elements of the innate immune system, responsible for triggering inflammation through the activation of caspase-1. Among them, the NLRP3 inflammasome plays a central role in various inflammatory and immune-related disorders. Dexketoprofen (DXK) is a widely used nonsteroidal anti-inflammatory drug (NSAID), although it has not been tested for its effects on the NLRP3 inflammasome pathway. In this study, we explored the influence of DXK on NLRP3 activation and its associated inflammatory responses in human macrophages. Our results showed that even at low concentrations, DXK enhances the release of IL-1β and promotes cell death upon stimulation with LPS and ATP, nigericin and LPS and nigericin, indicating it increases inflammasome activation. Docking and ATPase assays revealed that DXK binds to the NLRP3 NATCH domain, facilitating ATP hydrolysis and NLRP3 activation. Furthermore, treatment with DXK in combination with nigericin further increased IL-1β secretion, while the NLRP3 inhibitor MCC950 reduced the effects of DXK. These findings suggest that DXK amplifies inflammation in macrophages via NLRP3 activation, emphasizing the importance of caution in prolonged use, especially in autoinflammatory diseases where inflammasomes play a significant role.

The online version contains supplementary material available at 10.1007/s10787-025-01928-2.

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