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It has been suggested that the inhibition of extracellular calcium influx could potentially impede chondrocyte ferroptosis. The cystine transporter, solute carrier family 7 member 11 (SLC7A11), is recognized as a key regulator of ferroptosis. Recent studies suggest that the tumor suppressor gene p53 facilitates the induction of ferroptosis by suppressing the upregulation of SLC7A11. This process is mediated by the nuclear factor erythroid 2\u2010related factor 2 (NRF2), a key transcription factor integral to the maintenance of cellular redox homeostasis and the regulation of inflammatory responses. This study aims to investigate the role of ASIC1a in the ferroptosis of RA chondrocytes and to determine the involvement of the p53\/NRF2\/SLC7A11 pathway in its underlying mechanism. In\u00a0vitro experiments revealed that acidosis induces ferroptosis and reduces the expression of NRF2 and SLC7A11 in chondrocytes. Moreover, acidification significantly increased p53 protein levels in chondrocytes. Pifithrin\u2010\u03b1 (PFN\u2010\u03b1), a p53 inhibitor, mitigated acidosis\u2010induced ferroptosis and restored the diminished expression of NRF2 and SLC7A11. Furthermore, PcTx\u20101, an ASIC1a inhibitor, inhibited acidification\u2010induced ferroptosis, enhanced the protein levels of SLC7A11 and NRF2, and reduced p53 expression. In\u00a0vivo experiments demonstrated that the ASIC1a\u2010specific inhibitor PcTx\u20101 ameliorated histopathological characteristics of ankle joints in collagen\u2010induced arthritis (CIA) mice, decreased p53 expression, and enhanced NRF2 and SLC7A11 expression in chondrocytes. These findings suggest that ASIC1a inhibition may mitigate acidification\u2010induced ferroptosis in articular chondrocytes in RA, potentially via the p53\/NRF2\/SLC7A11 pathway.<\/jats:p>","DOI":"10.1096\/fj.202402134rr","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T05:41:14Z","timestamp":1736142074000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of\n                    <scp>ASIC1a<\/scp>\n                    reduces ferroptosis in rheumatoid arthritis articular chondrocytes via the p53\/\n                    <scp>NRF2<\/scp>\n                    \/\n                    <scp>SLC7A11<\/scp>\n                    pathway"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4211-7600","authenticated-orcid":false,"given":"Jie","family":"Tang","sequence":"first","affiliation":[{"name":"School of Pharmacy Anhui Medical University  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