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

Author

Listed:
  • Rui Wang

    (Tongji University)

  • Youwei Chen

    (Tongji University
    Tongji University)

  • Jiazhen Han

    (Tongji University)

  • Huikang Ye

    (Tongji University)

  • Huiran Yang

    (Tongji University)

  • Qianyan Li

    (Tongji University)

  • Yizhen He

    (Tongji University)

  • Boyu Ma

    (Tongji University)

  • Junjie Zhang

    (Tongji University)

  • Yanli Ge

    (Tongji University)

  • Zhe Wang

    (Tongji University)

  • Bo Sun

    (Tongji University)

  • Huahua Liu

    (Tongji University)

  • Liming Cheng

    (Tongji University
    Tongji University)

  • Zhirong Wang

    (Tongji University)

  • Gufa Lin

    (Tongji University
    Tongji University)

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.

Suggested Citation

  • 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, 2024. "Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-55295-7
    DOI: 10.1038/s41467-024-55295-7
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    References listed on IDEAS

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