Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure
Abstract Acute liver failure (ALF) is a hepatology emergency with rapid hepatic destruction, multiple organ failures, and high mortality. Despite decades of research, established ALF has minimal therapeutic options. Here, we report that the small bioactive compound SCM-198 increases the survival of...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55295-7 |
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| _version_ | 1846112424136015872 |
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| author | Rui Wang Youwei Chen Jiazhen Han Huikang Ye Huiran Yang Qianyan Li Yizhen He Boyu Ma Junjie Zhang Yanli Ge Zhe Wang Bo Sun Huahua Liu Liming Cheng Zhirong Wang Gufa Lin |
| author_facet | Rui Wang Youwei Chen Jiazhen Han Huikang Ye Huiran Yang Qianyan Li Yizhen He Boyu Ma Junjie Zhang Yanli Ge Zhe Wang Bo Sun Huahua Liu Liming Cheng Zhirong Wang Gufa Lin |
| author_sort | Rui Wang |
| collection | DOAJ |
| description | Abstract Acute liver failure (ALF) is a hepatology emergency with rapid hepatic destruction, multiple organ failures, and high mortality. Despite decades of research, established ALF has minimal therapeutic options. Here, we report that the small bioactive compound SCM-198 increases the survival of male ALF mice to 100%, even administered 24 hours after ALF establishment. We identify adiponectin receptor 2 (AdipoR2) as a selective target of SCM-198, with the AdipoR2 R335 residue being critical for the binding and signaling of SCM-198-AdipoR2 and AdipoR2 Y274 residue serving as a molecular switch for Ca2+ influx. SCM-198-AdipoR2 binding causes Ca2+ influx and elevates the phosphorylation levels of CaMKII and NOS3 in the AdipoR2-CaM-CaMKII-NOS3 complex identified in this study, rapidly inducing nitric oxide production for liver protection in murine ALF. SCM-198 also protects human ESC-derived liver organoids from APAP/TAA injuries. Thus, selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 is a rapid-acting therapeutic strategy for advanced ALF. |
| format | Article |
| id | doaj-art-899ae713e8fd4fc8a0b92b9b00ba4673 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-899ae713e8fd4fc8a0b92b9b00ba46732024-12-22T12:36:26ZengNature PortfolioNature Communications2041-17232024-12-0115112210.1038/s41467-024-55295-7Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failureRui Wang0Youwei Chen1Jiazhen Han2Huikang Ye3Huiran Yang4Qianyan Li5Yizhen He6Boyu Ma7Junjie Zhang8Yanli Ge9Zhe Wang10Bo Sun11Huahua Liu12Liming Cheng13Zhirong Wang14Gufa Lin15Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityDepartment of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji UniversityDepartment of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji UniversityDepartment of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji UniversityDepartment of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji UniversityDepartment of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityDepartment of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji UniversityKey Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji UniversityAbstract Acute liver failure (ALF) is a hepatology emergency with rapid hepatic destruction, multiple organ failures, and high mortality. Despite decades of research, established ALF has minimal therapeutic options. Here, we report that the small bioactive compound SCM-198 increases the survival of male ALF mice to 100%, even administered 24 hours after ALF establishment. We identify adiponectin receptor 2 (AdipoR2) as a selective target of SCM-198, with the AdipoR2 R335 residue being critical for the binding and signaling of SCM-198-AdipoR2 and AdipoR2 Y274 residue serving as a molecular switch for Ca2+ influx. SCM-198-AdipoR2 binding causes Ca2+ influx and elevates the phosphorylation levels of CaMKII and NOS3 in the AdipoR2-CaM-CaMKII-NOS3 complex identified in this study, rapidly inducing nitric oxide production for liver protection in murine ALF. SCM-198 also protects human ESC-derived liver organoids from APAP/TAA injuries. Thus, selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 is a rapid-acting therapeutic strategy for advanced ALF.https://doi.org/10.1038/s41467-024-55295-7 |
| spellingShingle | Rui Wang Youwei Chen Jiazhen Han Huikang Ye Huiran Yang Qianyan Li Yizhen He Boyu Ma Junjie Zhang Yanli Ge Zhe Wang Bo Sun Huahua Liu Liming Cheng Zhirong Wang Gufa Lin Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure Nature Communications |
| title | Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure |
| title_full | Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure |
| title_fullStr | Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure |
| title_full_unstemmed | Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure |
| title_short | Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure |
| title_sort | selectively targeting the adipor2 cam camkii nos3 axis by scm 198 as a rapid acting therapy for advanced acute liver failure |
| url | https://doi.org/10.1038/s41467-024-55295-7 |
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