The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism

  • Sci Rep. 2025 Jul 1;15(1):22067. doi: 10.1038/s41598-025-03419-4.
Shuai Shi  1  2 ,  Zhihui Qin  3 ,  Chang Liu  4 ,  Yanru Zhao  5 ,  Xiaopeng Bai  5 ,  Chaoyu Sun  5 ,  Xu Li  5 ,  Wanting Cong  5 ,  Xinyue Yuan  6 ,  Lixiu Sun  5 ,  Bingchen Liu  7  8  9 ,  Xueqi Li  10  11
Affiliations
  • 1. Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. [email protected].
  • 2. NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China. [email protected].
  • 3. Department of Obstetrics, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
  • 4. College of Pharmacy, Beihua University, Jilin, 132013, China.
  • 5. Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
  • 6. Beijing University of Chinese Medicine Dongfang College, Langfang, 065001, China.
  • 7. Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. [email protected].
  • 8. State Key Laboratory of Transvascular Implantation Devices, Hangzhou, 310009, China. [email protected].
  • 9. Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou, 310009, China. [email protected].
  • 10. Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. [email protected].
  • 11. NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China. [email protected].
PMID: 40593844 DOI: 10.1038/s41598-025-03419-4
Abstract

Doxorubicin (DOX) is an anthracycline class of chemotherapy drug, the application of which is limited due to its cardiotoxic effects. Recombinant Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), is a serine protease pivotal in lipid metabolism and has a profound correlation with the onset of cardiovascular diseases. This study uncovers a connection between PCSK9 and DOX-induced cardiotoxicity (DIC). This research found that injection of DOX in mice caused cardiac toxicity. DOX treatment up-regulated the expression of PCSK9 protein in myocardial tissue. Evolocumab (PCSK9 inhibitors) improved cardiac function, myocardial injury, and fibrosis in DOX-treated mice, indicating a protective effect against DIC. The mechanism involved modulation of cardiomyocyte Apoptosis and regulation of apoptosis-related proteins, including Bax/Bcl-2 ratio and Cleaved Caspase-3/Pro Caspase-3 ratio. DOX exhibited concentration- and time-dependent cytotoxic effects on H9C2 cardiomyocytes, promoting Apoptosis. PCSK9 nuclear aggregation occurred in H9C2 cardiomyocytes after DOX treatment, and PCSK9 interacted with the Importin subunit beta-1 (KPNB1) protein. Interference with PCSK9 up-regulated KPNB1 expression, affecting apoptosis-related proteins and improving DOX-induced H9C2 cardiomyocyte Apoptosis. In short, the elucidation of this mechanism is helpful involve that PCSK9 Inhibitor may be a potential drug for improving DIC.

Keywords
Apoptosis; Cardiotoxicity; Doxorubicin; KPNB1; PCSK9.
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