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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-1\u03b2 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-1\u03b2 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.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10787-025-01928-2","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T16:06:59Z","timestamp":1758643619000},"page":"6089-6098","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dexketoprofen enhances NLRP3 activation via ATPase activity after canonical stimuli"],"prefix":"10.1007","volume":"33","author":[{"given":"Daniel","family":"Boy-Ruiz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Miguel","family":"Suarez-Rivero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e9s","family":"Muela-Zarzuela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0151-3644","authenticated-orcid":false,"given":"Mario D.","family":"Cordero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"issue":"8","key":"1928_CR1","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1111\/j.1365-2036.2007.03292.x","volume":"25","author":"NS Abraham","year":"2007","unstructured":"Abraham NS, El-Serag HB, Hartman C, Richardson P, Deswal A (2007) Cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction and cerebrovascular accident. 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