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Inhibition of the P2Y12 receptors reduced iron overload in macrophages displaying an anti-inflammatory response. Herein, the ameliorative effect of ticagrelor, a reversible P2Y12 inhibitor, against adjuvant-induced arthritis (AIA) in rats was investigated, with a special emphasis on the possible modulation of some inflammatory signals linked to ferroptosis. Particularly, correlation analyses were conducted between nod-like receptor protein 3 (NLRP3) and all assessed parameters. Four groups of rats were assigned: Control group, AIA group (0.1\u00a0ml intradermal injection of complete Freund's adjuvant), Ticagrelor group (30\u00a0mg\/kg, p.o.), and Ticagrelor\u2009+\u2009AIA group. Ticagrelor exhibited an anti-arthritic effect, evidenced by significant improvements in both macroscopic and histopathological alterations. It effectively inhibited ferroptosis, indicated by a marked upregulation of the ferroptotic inhibitors, solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) to reach 9.80, 2.20, and 8.49-folds (p\u2009&lt;\u20090.0001), along with a notable reduction in the ferroptotic promoters, P53, acyl-CoA synthetase long-chain family member 4 (ACSL4) and arachidonic acid 15-lipoxygenase-1 (ALOX15) by 89.46%, 41.45% and 49.85% (p\u2009&lt;\u20090.0001). It reduced TNF-\u03b1 and various chemokines (RANTES, MIP-1\u03b1, eotaxin-3) to suppress matrix metalloproteinases expression. Furthermore, ticagrelor decreased NLRP3 expression by 48.63% (p\u2009&lt;\u20090.0001) to pinpoint its anti-inflammatory effect. Overall, amending the P53\/SLC7A11\/ALOX15 axis by ticagrelor mediated its anti-inflammatory and anti-ferroptotic effects. These findings provide preliminary experimental evidences for further investigating the potential impacts of ticagrelor as a treatment for RA.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s10787-025-01841-8","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T12:06:20Z","timestamp":1751889980000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Crosstalk between ferroptosis and NLRP3, a possible therapeutic target in experimentally-induced rheumatoid arthritis: role of P2Y12R inhibition in modulating P53\/SLC7A11\/ALOX15 signaling"],"prefix":"10.1007","author":[{"given":"Fatma S.","family":"Eltyar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1601-6608","authenticated-orcid":false,"given":"Dalia M.","family":"El-Tanbouly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala F.","family":"Zaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehab M.","family":"El-Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"1841_CR1","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.3389\/fimmu.2017.01341","volume":"8","author":"SA Agere","year":"2017","unstructured":"Agere SA, Akhtar N, Watson JM, Ahmed S (2017) RANTES\/CCL5 induces collagen degradation by activating MMP-1 and MMP-13 expression in human rheumatoid arthritis synovial fibroblasts. 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