Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injury
Abstract Hepatic ischemia-reperfusion injury (HIRI) is a critical condition that often occurs during liver transplantation and surgical liver resection. However, its mechanism has not been fully elucidated. Nicotinamide adenine dinucleotide (NAD+), functioning as a coenzyme or cofactor, is crucial f...
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Nature Publishing Group
2025-05-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02233-8 |
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| author | Qi-Hang Zhao Ya-Ting Zhang Ke Wen Qi Ding Zi-Ying Chen Dilinuer Tula Jia-Hui Li Juan Zhou Yun-Fei Xiao Xiao-Hui Guan Ke-Yu Deng Ling-Fang Wang Hong-Bo Xin |
| author_facet | Qi-Hang Zhao Ya-Ting Zhang Ke Wen Qi Ding Zi-Ying Chen Dilinuer Tula Jia-Hui Li Juan Zhou Yun-Fei Xiao Xiao-Hui Guan Ke-Yu Deng Ling-Fang Wang Hong-Bo Xin |
| author_sort | Qi-Hang Zhao |
| collection | DOAJ |
| description | Abstract Hepatic ischemia-reperfusion injury (HIRI) is a critical condition that often occurs during liver transplantation and surgical liver resection. However, its mechanism has not been fully elucidated. Nicotinamide adenine dinucleotide (NAD+), functioning as a coenzyme or cofactor, is crucial for both redox and non-redox processes. In mammals, CD38 serves as the primary enzyme responsible for NAD+ degradation. In this study, we reported that the absence of CD38 markedly reduces HIRI in CD38 global knockout (CD38KO) and CD38 myeloid-specific knockout (CD38MKO) mice, but not in CD38 hepatocyte-specific knockout (CD38LKO) mice compared with the control (CD38fl/fl) mice by suppressing HIRI-induced hepatic oxidative stress, inflammatory responses, and pyroptosis. The findings were corroborated by a noticeable decrease in levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH), along with reduced necrosis. Besides, we found that the expressions of SIRT1 and its downstream targets, p53 and PPARγ, were elevated in the liver tissues of CD38KO and CD38MKO mice compared to CD38fl/fl mice, while the acetylation levels of p53 were reduced. Furthermore, we demonstrated that myeloid CD38 deficiency not only promoted M2-type polarization and inhibited M1-type polarization of macrophages but also suppressed NLRP3-mediated pyroptosis by triggering NAD+/SIRT1 signaling in macrophages, resulting in the reduction of oxidative stress, inflammation, and pyroptosis in the liver, ultimately protecting against HIRI. This study highlights myeloid CD38 as a promising target for the prevention and treatment of HIRI clinically. |
| format | Article |
| id | doaj-art-5a0593f0a58c44cf8c8e1aee9b3accb6 |
| institution | OA Journals |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-5a0593f0a58c44cf8c8e1aee9b3accb62025-08-20T02:15:11ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-05-0110111310.1038/s41392-025-02233-8Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injuryQi-Hang Zhao0Ya-Ting Zhang1Ke Wen2Qi Ding3Zi-Ying Chen4Dilinuer Tula5Jia-Hui Li6Juan Zhou7Yun-Fei Xiao8Xiao-Hui Guan9Ke-Yu Deng10Ling-Fang Wang11Hong-Bo Xin12National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityDepartment of Gynecology and Obstetrics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityNational Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang UniversityAbstract Hepatic ischemia-reperfusion injury (HIRI) is a critical condition that often occurs during liver transplantation and surgical liver resection. However, its mechanism has not been fully elucidated. Nicotinamide adenine dinucleotide (NAD+), functioning as a coenzyme or cofactor, is crucial for both redox and non-redox processes. In mammals, CD38 serves as the primary enzyme responsible for NAD+ degradation. In this study, we reported that the absence of CD38 markedly reduces HIRI in CD38 global knockout (CD38KO) and CD38 myeloid-specific knockout (CD38MKO) mice, but not in CD38 hepatocyte-specific knockout (CD38LKO) mice compared with the control (CD38fl/fl) mice by suppressing HIRI-induced hepatic oxidative stress, inflammatory responses, and pyroptosis. The findings were corroborated by a noticeable decrease in levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH), along with reduced necrosis. Besides, we found that the expressions of SIRT1 and its downstream targets, p53 and PPARγ, were elevated in the liver tissues of CD38KO and CD38MKO mice compared to CD38fl/fl mice, while the acetylation levels of p53 were reduced. Furthermore, we demonstrated that myeloid CD38 deficiency not only promoted M2-type polarization and inhibited M1-type polarization of macrophages but also suppressed NLRP3-mediated pyroptosis by triggering NAD+/SIRT1 signaling in macrophages, resulting in the reduction of oxidative stress, inflammation, and pyroptosis in the liver, ultimately protecting against HIRI. This study highlights myeloid CD38 as a promising target for the prevention and treatment of HIRI clinically.https://doi.org/10.1038/s41392-025-02233-8 |
| spellingShingle | Qi-Hang Zhao Ya-Ting Zhang Ke Wen Qi Ding Zi-Ying Chen Dilinuer Tula Jia-Hui Li Juan Zhou Yun-Fei Xiao Xiao-Hui Guan Ke-Yu Deng Ling-Fang Wang Hong-Bo Xin Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injury Signal Transduction and Targeted Therapy |
| title | Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injury |
| title_full | Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injury |
| title_fullStr | Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injury |
| title_full_unstemmed | Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injury |
| title_short | Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injury |
| title_sort | myeloid but not hepatocytic cd38 is a key driver for hepatic ischemia reperfusion injury |
| url | https://doi.org/10.1038/s41392-025-02233-8 |
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