biostudies-literatureGao XHeilongjiang Graduate Excellence Funding ProgramNational Natural Science Foundation of Chinathe Natural Science Foundation of Heilongjiange05270https://www.ebi.ac.uk/biostudies/studies/S-EPMC12631900biostudies-literatureUnknown12(43)The clinical utility of the anticancer agent doxorubicin (DOX) is limited by its dose-dependent cardiotoxicity. ALYREF, a nuclear protein that preserves genomic stability through interactions with intranuclear components or as an m⁵C-binding regulator of mRNA maturation and export, has not been previously implicated in DOX-induced cardiotoxicity (DIC). Here, the role and underlying mechanisms of ALYREF in the pathogenesis of DIC are investigated. The findings demonstrate that ALYREF expression is markedly reduced in a murine model of DIC. Myocardial-specific overexpression of ALYREF attenuates DOX-induced DNA damage and cardiomyocyte apoptosis, whereas cardiac-specific knockout of ALYREF (ALYREF CKO) exacerbates DOX-induced cardiac dysfunction. Mechanistically, it is identified that nucleaAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Preservation of ALYREF Phase Separation Mitigates Doxorubicin-Induced Cardiomyocyte DNA Damage and Cardiotoxicity.PMC1263190082400418PL2024H083LJYXL2024-072ZL2024H017;PL2024H08382373958ZL2024H0178247026682500435Li HYu LPan ZGong RXiao ZRen ZYang BHan ZMa WLiu XCai BCai ALiu YLian GTian YZagidullin NGao XWang XShen YfalsePreservation of ALYREF Phase Separation Mitigates Doxorubicin-Induced Cardiomyocyte DNA Damage and Cardiotoxicity.The clinical utility of the anticancer agent doxorubicin (DOX) is limited by its dose-dependent cardiotoxicity. ALYREF, a nuclear protein that preserves genomic stability through interactions with intranuclear components or as an m⁵C-binding regulator of mRNA maturation and export, has not been previously implicated in DOX-induced cardiotoxicity (DIC). Here, the role and underlying mechanisms of ALYREF in the pathogenesis of DIC are investigated. The findings demonstrate that ALYREF expression is markedly reduced in a murine model of DIC. Myocardial-specific overexpression of ALYREF attenuates DOX-induced DNA damage and cardiomyocyte apoptosis, whereas cardiac-specific knockout of ALYREF (ALYREF CKO) exacerbates DOX-induced cardiac dysfunction. Mechanistically, it is identified that nuclea2025-01-01T00:00:00Z2025 Nov2026-06-05T17:07:35.571Z2026-05-19T03:12:02.861ZS-EPMC126319004089952010.1002/advs.202505270