MSCs Suppress Macrophage Necroptosis and Foster Liver Regeneration by Modulating SP1/SK1 Axis in Treating Acute Severe Autoimmune Hepatitis

Abstract Acute severe autoimmune hepatitis (AS‐AIH) is characterized by rapid progression and poor prognosis, with a current lack of effective targeted treatments. Stem cell therapy has demonstrated significant therapeutic promise across various autoimmune diseases. However, the intricate pathogenesis of AS‐AIH has hindered the widespread utilization of mesenchymal stem cells (MSCs) in this domain. Herein, it is demonstrated that necroptosis, as the primary mode of cell death in AIH, is crucial in causing AS‐AIH. Inflammatory macrophages are the primary cell population involved in necroptosis. Inhibition of the specificity protein 1/sphingosine kinase 1/sphingosine‐1‐phosphate (SP1/SK1/S1P) axis is responsible for this phenomenon, leading to excessive activation of the intrahepatic immune system and aggravating liver damage. Furthermore, the S1P/S1PR2/YAP axis is the key pathway in initiating liver regeneration during AS‐AIH. S1P synthesized by hepatocytes is the primary source, and this process is also regulated by the SP1/SK1 axis. MSCs promote S1P synthesis by macrophages through the delivery of SP1, which inhibits necroptosis and synergistically enhances liver regeneration. In addition, MSCs also promote S1P synthesis in hepatocytes through the same mechanism, further aiding liver regeneration. These findings unveil the core pathogenesis of AS‐AIH and provide a theoretical foundation for using MSCs as a potential targeted therapeutic modality.