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Author Spotlight: Evaluating Therapeutic Strategies to Enhance Liver Regeneration
Published on: May 24, 2024
Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver
Rui Wang1, Youwei Chen1,2, Jiazhen Han1
1Key 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.
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.
Insights
A novel compound, SCM-198, offers a 100% survival rate in mice with acute liver failure (ALF) by targeting the AdipoR2 receptor. This breakthrough provides a potential rapid treatment for advanced ALF.
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Acute liver failure (ALF) is a critical medical condition characterized by rapid liver damage, multi-organ failure, and high mortality rates.
- Current therapeutic options for established ALF are limited, highlighting the urgent need for effective treatments.
Purpose of the Study:
- To investigate the therapeutic potential of the small bioactive compound SCM-198 in treating acute liver failure.
- To identify the molecular target and mechanism of action of SCM-198 in liver protection.
Main Methods:
- Administration of SCM-198 to male ALF mice, assessing survival rates at 24 hours post-treatment.
- Identification of SCM-198's molecular target using biochemical assays and structural analysis (AdipoR2 R335 and Y274 residues).
- Analysis of intracellular signaling pathways (Ca2+ influx, CaMKII, NOS3 phosphorylation) and nitric oxide production.
- Testing SCM-198 efficacy on human liver organoids subjected to APAP/TAA-induced injury.
Main Results:
- SCM-198 administration resulted in 100% survival in male ALF mice, even when given 24 hours after ALF onset.
- Adiponectin receptor 2 (AdipoR2) was identified as the selective target of SCM-198, with specific residues (R335, Y274) crucial for its action.
- SCM-198 binding to AdipoR2 triggered Ca2+ influx and activated the AdipoR2-CaM-CaMKII-NOS3 complex, leading to rapid nitric oxide production.
- SCM-198 demonstrated protective effects against acetaminophen (APAP) and thioacetamide (TAA) induced injuries in human liver organoids.
Conclusions:
- SCM-198 represents a highly effective therapeutic strategy for advanced acute liver failure, achieving complete survival in a murine model.
- The compound selectively targets the AdipoR2 receptor, modulating the Ca2+-CaMKII-NOS3 signaling axis to induce rapid liver protection.
- SCM-198 shows promise as a rapid-acting treatment for ALF, with demonstrated efficacy in both animal models and human-derived organoids.
