{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T05:20:33Z","timestamp":1787721633255,"version":"build-2784847793"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"13","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">The clinical utility of doxorubicin, a potent chemotherapeutic agent, is severely limited by its dose\u2010dependent cardiotoxicity. Hypoxia\u2010inducible factor 1\u03b1 (HIF1\u03b1) is a key regulator of cardiovascular adaptation, but its role and mechanism in doxorubicin\u2010induced cardiotoxicity (DIC) remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Using in\u00a0vitro (AC16 cells) and in\u00a0vivo (mouse) models of DIC, we used genetic (knockout, knockdown) and pharmacological (FG4592) approaches to modulate HIF1\u03b1. Cardiac function, apoptosis, endoplasmic reticulum (ER) morphology, and ER\u2010phagy flux were assessed. Molecular mechanisms were investigated using chromatin immunoprecipitation and promoter activity assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      HIF1\u03b1 exhibited a dynamic, biphasic expression pattern during DIC progression. Stabilization of HIF1\u03b1 by FG4592 alleviated doxorubicin\u2010induced cardiac dysfunction, atrophy, fibrosis, and apoptosis, whereas HIF1\u03b1 knockout exacerbated these injuries. The protective effects of FG4592 were strictly dependent on HIF1\u03b1. Mechanistically, HIF1\u03b1 transcriptionally activated the ER\u2010phagy receptor gene testis\u2010expressed protein 264 (\n                      <jats:italic toggle=\"no\">TEX264<\/jats:italic>\n                      ) by directly binding to its promoter. This activation enhanced ER\u2010phagy, and suppressed ER stress\u2013mediated apoptosis. Crucially, ablation of\n                      <jats:italic toggle=\"no\">TEX264<\/jats:italic>\n                      abolished the cardioprotective effects of both HIF1\u03b1 and FG4592.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">This study identifies a novel HIF1\u03b1\/TEX264\/ER\u2010phagy axis that is suppressed in DIC and is central to cardiomyocyte survival. Targeting this pathway, particularly with the clinically available HIF1\u03b1 stabilizer FG4592, represents a promising therapeutic strategy against DIC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.047158","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:18:00Z","timestamp":1783073880000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["HIF1\u03b1 Attenuates Doxorubicin\u2010Induced Cardiotoxicity by Activating TEX264\u2010Associated ER\u2010phagy"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5102-5238","authenticated-orcid":false,"given":"Xinying","family":"Wang","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Dalian Medical University","place":["Dalian, China"]},{"name":"The First Affiliated Hospital of Dalian Medical University","place":["Dalian, 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