Histidine triad nucleotide‐binding protein 2 attenuates doxorubicin‐induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice
Abstract Doxorubicin (DOX) is an effective chemotherapy drug widely used against various cancers but is limited by severe cardiotoxicity. Mitochondria–lysosome interactions are crucial for cellular homeostasis. This study investigates the role of histidine triad nucleotide‐binding protein 2 (HINT2)...
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Wiley
2025-03-01
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| Online Access: | https://doi.org/10.1002/mco2.70075 |
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| author | Hao Jiang Jinyan Zhang Daile Jia Liwei Liu Jinfeng Gao Beijian Zhang Zhen Dong Xiaolei Sun Wenlong Yang Tiantong Ou Suling Ding Luna He Yiqin Shi Kai Hu Aijun Sun Junbo Ge |
| author_facet | Hao Jiang Jinyan Zhang Daile Jia Liwei Liu Jinfeng Gao Beijian Zhang Zhen Dong Xiaolei Sun Wenlong Yang Tiantong Ou Suling Ding Luna He Yiqin Shi Kai Hu Aijun Sun Junbo Ge |
| author_sort | Hao Jiang |
| collection | DOAJ |
| description | Abstract Doxorubicin (DOX) is an effective chemotherapy drug widely used against various cancers but is limited by severe cardiotoxicity. Mitochondria–lysosome interactions are crucial for cellular homeostasis. This study investigates the role of histidine triad nucleotide‐binding protein 2 (HINT2) in DOX‐induced cardiotoxicity (DIC). We found that HINT2 expression was significantly upregulated in the hearts of DOX‐treated mice. Cardiac‐specific Hint2 knockout mice exhibited significantly worse cardiac dysfunction, impaired autophagic flux, and lysosomal dysfunction after DOX treatment. Mechanistically, HINT2 deficiency reduced oxidative phosphorylation complex I activity and disrupted the nicotinamide adenine dinucleotide NAD+/NADH ratio, impairing lysosomal function. Further, HINT2 deficiency suppressed sterol regulatory element binding protein 2 activity, downregulating transcription factor A mitochondrial, a critical regulator of complex I. Nicotinamide mononucleotide (NMN) supplementation restored lysosomal function in vitro, while cardiac‐specific Hint2 overexpression using adeno‐associated virus 9 or adenovirus alleviated DIC both in vivo and in vitro. These findings highlight HINT2 as a key cardioprotective factor that mitigates DIC by restoring the NAD+/NADH ratio, lysosomal function, and autophagy. Therapeutic strategies enhancing HINT2 expression or supplementing NMN may reduce cardiac damage and heart failure caused by DOX. |
| format | Article |
| id | doaj-art-ee486277157545989d77c4ae95e654f4 |
| institution | DOAJ |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-ee486277157545989d77c4ae95e654f42025-08-20T02:40:30ZengWileyMedComm2688-26632025-03-0163n/an/a10.1002/mco2.70075Histidine triad nucleotide‐binding protein 2 attenuates doxorubicin‐induced cardiotoxicity through restoring lysosomal function and promoting autophagy in miceHao Jiang0Jinyan Zhang1Daile Jia2Liwei Liu3Jinfeng Gao4Beijian Zhang5Zhen Dong6Xiaolei Sun7Wenlong Yang8Tiantong Ou9Suling Ding10Luna He11Yiqin Shi12Kai Hu13Aijun Sun14Junbo Ge15Department of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Nephrology Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Nephrology Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaDepartment of Cardiology Zhongshan Hospital Fudan University Shanghai Institute of Cardiovascular Diseases Shanghai Shanghai ChinaAbstract Doxorubicin (DOX) is an effective chemotherapy drug widely used against various cancers but is limited by severe cardiotoxicity. Mitochondria–lysosome interactions are crucial for cellular homeostasis. This study investigates the role of histidine triad nucleotide‐binding protein 2 (HINT2) in DOX‐induced cardiotoxicity (DIC). We found that HINT2 expression was significantly upregulated in the hearts of DOX‐treated mice. Cardiac‐specific Hint2 knockout mice exhibited significantly worse cardiac dysfunction, impaired autophagic flux, and lysosomal dysfunction after DOX treatment. Mechanistically, HINT2 deficiency reduced oxidative phosphorylation complex I activity and disrupted the nicotinamide adenine dinucleotide NAD+/NADH ratio, impairing lysosomal function. Further, HINT2 deficiency suppressed sterol regulatory element binding protein 2 activity, downregulating transcription factor A mitochondrial, a critical regulator of complex I. Nicotinamide mononucleotide (NMN) supplementation restored lysosomal function in vitro, while cardiac‐specific Hint2 overexpression using adeno‐associated virus 9 or adenovirus alleviated DIC both in vivo and in vitro. These findings highlight HINT2 as a key cardioprotective factor that mitigates DIC by restoring the NAD+/NADH ratio, lysosomal function, and autophagy. Therapeutic strategies enhancing HINT2 expression or supplementing NMN may reduce cardiac damage and heart failure caused by DOX.https://doi.org/10.1002/mco2.70075autophagydoxorubicinHINT2lysosomeNAD+/NADH |
| spellingShingle | Hao Jiang Jinyan Zhang Daile Jia Liwei Liu Jinfeng Gao Beijian Zhang Zhen Dong Xiaolei Sun Wenlong Yang Tiantong Ou Suling Ding Luna He Yiqin Shi Kai Hu Aijun Sun Junbo Ge Histidine triad nucleotide‐binding protein 2 attenuates doxorubicin‐induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice MedComm autophagy doxorubicin HINT2 lysosome NAD+/NADH |
| title | Histidine triad nucleotide‐binding protein 2 attenuates doxorubicin‐induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice |
| title_full | Histidine triad nucleotide‐binding protein 2 attenuates doxorubicin‐induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice |
| title_fullStr | Histidine triad nucleotide‐binding protein 2 attenuates doxorubicin‐induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice |
| title_full_unstemmed | Histidine triad nucleotide‐binding protein 2 attenuates doxorubicin‐induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice |
| title_short | Histidine triad nucleotide‐binding protein 2 attenuates doxorubicin‐induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice |
| title_sort | histidine triad nucleotide binding protein 2 attenuates doxorubicin induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice |
| topic | autophagy doxorubicin HINT2 lysosome NAD+/NADH |
| url | https://doi.org/10.1002/mco2.70075 |
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