The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism
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 o...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-03419-4 |
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| author | Shuai Shi Zhihui Qin Chang Liu Yanru Zhao Xiaopeng Bai Chaoyu Sun Xu Li Wanting Cong Xinyue Yuan Lixiu Sun Bingchen Liu Xueqi Li |
| author_facet | Shuai Shi Zhihui Qin Chang Liu Yanru Zhao Xiaopeng Bai Chaoyu Sun Xu Li Wanting Cong Xinyue Yuan Lixiu Sun Bingchen Liu Xueqi Li |
| author_sort | Shuai Shi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1111520d0b7b4d45aa72eedd4f4f5232 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-1111520d0b7b4d45aa72eedd4f4f52322025-08-20T03:45:24ZengNature PortfolioScientific Reports2045-23222025-07-0115111910.1038/s41598-025-03419-4The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanismShuai Shi0Zhihui Qin1Chang Liu2Yanru Zhao3Xiaopeng Bai4Chaoyu Sun5Xu Li6Wanting Cong7Xinyue Yuan8Lixiu Sun9Bingchen Liu10Xueqi Li11Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical UniversityDepartment of Obstetrics, The Fourth Affiliated Hospital of Harbin Medical UniversityCollege of Pharmacy, Beihua UniversityDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical UniversityBeijing University of Chinese Medicine Dongfang CollegeDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical UniversityAbstract 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.https://doi.org/10.1038/s41598-025-03419-4DoxorubicinPCSK9KPNB1ApoptosisCardiotoxicity |
| spellingShingle | Shuai Shi Zhihui Qin Chang Liu Yanru Zhao Xiaopeng Bai Chaoyu Sun Xu Li Wanting Cong Xinyue Yuan Lixiu Sun Bingchen Liu Xueqi Li The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism Scientific Reports Doxorubicin PCSK9 KPNB1 Apoptosis Cardiotoxicity |
| title | The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism |
| title_full | The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism |
| title_fullStr | The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism |
| title_full_unstemmed | The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism |
| title_short | The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism |
| title_sort | function of pcsk9 in doxorubicin induced cardiotoxicity and its underlying mechanism |
| topic | Doxorubicin PCSK9 KPNB1 Apoptosis Cardiotoxicity |
| url | https://doi.org/10.1038/s41598-025-03419-4 |
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