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.

急性肝衰竭 （ALF） 是一种肝脏急症，具有快速的肝脏破坏、多器官衰竭和高死亡率。尽管进行了数十年的研究，但已建立的 ALF 的治疗选择很少。在这里，我们报道了小生物活性化合物 SCM-198 将雄性 ALF 小鼠的存活率提高到 100%，即使在 ALF 建立后 24 小时给药也是如此。我们确定脂联素受体 2 （AdipoR2） 是 SCM-198 的选择性靶标，其中 AdipoR2 R335 残基对 SCM-198-AdipoR2 和 AdipoR2 Y274 残基的结合和信号传导至关重要，可作为 Ca²⁺ 内流的分子开关。SCM-198-AdipoR2 结合导致 Ca²⁺ 内流，并升高本研究中发现的 AdipoR2-CaM-CaMKII-NOS3 复合物中 CaMKII 和 NOS3 的磷酸化水平，迅速诱导一氧化氮产生以保护小鼠 ALF 的肝脏。SCM-198 还可以保护人 ESC 来源的肝脏类器官免受 APAP/TAA 损伤。因此，SCM-198 选择性靶向 AdipoR2-CaM-CaMKII-NOS3 轴是晚期 ALF 的快速治疗策略。