2. Academic Validation
  3. Preservation of ALYREF Phase Separation Mitigates Doxorubicin-Induced Cardiomyocyte DNA Damage and Cardiotoxicity

Preservation of ALYREF Phase Separation Mitigates Doxorubicin-Induced Cardiomyocyte DNA Damage and Cardiotoxicity

  • Adv Sci (Weinh). 2025 Sep 3:e05270. doi: 10.1002/advs.202505270.
Xinlu Gao 1 2,  Yifu Shen 3,  Zhihui Xiao 1 2,  Zhenbo Han 4,  Xu Liu 3,  Ao Cai 1 2,  Yanan Tian 1 2,  Guang Lian 1 2,  Wenya Ma 1 2,  Yining Liu 1 2,  Rui Gong 5,  Hanjing Li 1 2,  Xiuxiu Wang 1 2,  Zhongyu Ren 1 2,  Naufal Zagidullin 6,  Lei Yu 7,  Ye Tian 8,  Yu Liu 3,  Zhenwei Pan 2,  Baofeng Yang 2,  Benzhi Cai 1 2 9
Affiliations

Affiliations

  • 1 Department of Pharmacy at the Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, China.
  • 2 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
  • 3 Department of Laboratory Medicine at The Fourth Affiliated Hospital, Harbin Medical University, Harbin, 150023, China.
  • 4 Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA.
  • 5 Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, 710032, China.
  • 6 Department of Internal Diseases, Bashkir State Medical University, Ufa, 450008, Russia.
  • 7 Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
  • 8 Department of Pathophysiology and the Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Harbin, 150081, China.
  • 9 Institute of Clinical Pharmacy, NHC Key Laboratory of Cell Transplantation, the Heilongjiang Key Laboratory of Drug Research, Harbin Medical University, Harbin, 150081, China.
PMID: 40899520 DOI: 10.1002/advs.202505270
Abstract

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 nuclear DOX directly binds to the aspartate residue (D171) within the intrinsically disordered regions (IDRs) of ALYREF, disrupting its liquid-liquid phase separation (LLPS) and promoting its ubiquitin-mediated degradation. The condensate state of ALYREF is essential for maintaining the integrity of the NORAD-activated ribonucleoprotein complex 1 (NARC1). Consequently, disruption of ALYREF LLPS leads to dissociation of the NARC1 complex, resulting in DNA damage and Apoptosis in CMs. Collectively, these findings reveal a previously unrecognized mechanism by which DIC via interference with ALYREF condensates, offering new insight into the molecular basis of DIC.

Keywords

ALYREF; DNA damage; cardiotoxicity; doxorubicin; liquid–liquid phase separation.

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