Wang Rui, Chen Youwei, Han Jiazhen, Ye Huikang, Yang Huiran, Li Qianyan, He Yizhen, Ma Boyu, Zhang Junjie, Ge Yanli, Wang Zhe, Sun Bo, Liu Huahua, Cheng Liming, Wang Zhirong, Lin Gufa
Key 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 University, Shanghai, China.
School of Medicine, Tongji University, Shanghai, China.
Nat Commun. 2024 Dec 16;15(1):10690. doi: 10.1038/s41467-024-55295-7.
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 Ca influx. SCM-198-AdipoR2 binding causes Ca 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.
急性肝衰竭（ALF）是一种肝脏科急症，伴有肝脏迅速破坏、多器官功能衰竭和高死亡率。尽管经过数十年研究，但对于已确诊的ALF，治疗选择极少。在此，我们报告小生物活性化合物SCM - 198可使雄性ALF小鼠的存活率提高至100%，即使在ALF发病24小时后给药也是如此。我们确定脂联素受体2（AdipoR2）是SCM - 198的选择性靶点，AdipoR2的R335残基对于SCM - 198与AdipoR2的结合及信号传导至关重要，而AdipoR2的Y274残基作为钙离子内流的分子开关。SCM - 198与AdipoR2的结合导致钙离子内流，并提高本研究中鉴定的AdipoR2 - CaM - CaMKII - NOS3复合物中CaMKII和NOS3的磷酸化水平，迅速诱导一氧化氮生成以保护小鼠ALF中的肝脏。SCM - 198还可保护人胚胎干细胞衍生的肝类器官免受对乙酰氨基酚/硫代乙酰胺损伤。因此，通过SCM - 198选择性靶向AdipoR2 - CaM - CaMKII - NOS3轴是晚期ALF的一种速效治疗策略。
