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Upon cellular injury, hypoxia, or necrosis, substantial quantities of ATP efflux into the extracellular space, activating P2X<jats:sub>7<\/jats:sub> receptors, thereby initiating multiple signaling cascades. In vivo studies demonstrated coordinated upregulation of P2X<jats:sub>7<\/jats:sub> and autophagy\u2010related proteins in the infarcted border zone. Transcriptome sequencing revealed Nox4 overexpression in the myocardial tissue post\u2010infarction; furthermore, administration of the P2X<jats:sub>7<\/jats:sub> receptor antagonist A740003 effectively reduced both autophagy\u2010related protein levels and Nox4 expression. In vitro experiments indicated that hypoxia induced upregulation of Nox4, p\u2010PERK\/PERK, ATF4, Beclin\u20101, and ATG5 in cardiomyocytes, A740003 could inhibit the expression of these proteins, while overexpression of Nox4 counteracted this effect. Collectively, our findings indicated that the P2X<jats:sub>7<\/jats:sub> receptor expression was elevated in the infarcted border zone following MI and implicated its role in excessive autophagy induced by hypoxia in cardiomyocytes\u2014at least partially through the Nox4\/PERK\/ATF4 pathway, thereby exacerbating myocardial injury following MI.<\/jats:p>","DOI":"10.1002\/cbf.70078","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T03:40:58Z","timestamp":1745811658000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["P2X<sub>7<\/sub> Receptor Facilitates Cardiomyocyte Autophagy After Myocardial Infarction via Nox4\/PERK\/ATF4 Signaling Pathway"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1123-0206","authenticated-orcid":false,"given":"Shuhong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology Renmin 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