Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure

Nature Communications, 2024 · DOI: 10.1038/s41467-024-55295-7 · Published: December 8, 2024

Simple Explanation

Acute liver failure (ALF) is a severe condition with limited treatment options. This study identifies a compound, SCM-198, that significantly improves survival in mice with ALF, even when administered a day after the condition is established. SCM-198 works by targeting a specific protein receptor, AdipoR2, and triggering a cascade of molecular events that lead to liver protection. This includes calcium influx and nitric oxide production. The compound was also effective in protecting human liver organoids from damage, suggesting its potential as a therapeutic strategy for advanced ALF in humans.

Study Duration

Not specified

Participants

Male adult C57BL/6 J mice, human liver organoids

Evidence Level

Not specified

Key Findings

1
SCM-198 treatment resulted in a 100% survival rate in murine ALF models, even when administered 24 hours after ALF was established.
2
AdipoR2 was identified as a selective target of SCM-198, with specific residues (R335 and Y274) being critical for the binding and signaling of SCM-198.
3
SCM-198 induces Ca2+ influx and elevates the phosphorylation levels of CaMKII and NOS3, leading to rapid nitric oxide production for liver protection.

Research Summary

The study identifies SCM-198 as a potential therapeutic agent for advanced acute liver failure (ALF). SCM-198 demonstrates a remarkable 100% survival rate in murine ALF models, even when administered 24 hours post-intoxication. SCM-198 selectively targets the adiponectin receptor AdipoR2, triggering a cascade involving Ca2+ influx, CaMKII and NOS3 phosphorylation, and nitric oxide production, ultimately protecting the liver. Functional analysis in Adipor2-/- and Nos3-/- mice and human liver organoids further supports the conclusion that selectively targeting the AdipoR2-CaM-CamKII-NOS3 axis is a rapid-acting therapeutic strategy for advanced ALF.

Practical Implications

Therapeutic Potential

SCM-198 could be a novel therapeutic strategy for advanced ALF, potentially extending the treatment window and improving patient outcomes.

Drug Target Discovery

AdipoR2 is validated as a drug target for ALF, offering a new avenue for developing targeted therapies.

Underlying Mechanism

The study elucidates the molecular mechanisms underlying SCM-198's hepatoprotective effects, providing insights for future drug development efforts.

Study Limitations

1
The study is primarily conducted in murine models, and further research is needed to confirm the efficacy and safety of SCM-198 in human clinical trials.
2
The specific binding target of SCM-198 was undetermined for years, hindering its translational applications.
3
Further cryo-EM study would provide more structural bases for the R335-SCM-198 interaction and address whether the structural difference between AdipoR2 and AdipoR1 accounts for the selectivity of binding of SCM-198 to AdipoR2.

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