MacroH2A S-sulfhydration Alleviates Liver Injury by Inhibiting the Inflammatory Response of Macrophages
Description
The progression of liver disease critically depends on the activation and recruitment of hepatic macrophages, a process orchestrated by various non-parenchymal cells. Protein S-sulfhydration mediated by H2S has been shown to play important roles in several diseases. However, the precise mechanisms by which H2S affects liver injury through macrophages remain unclear. This study reveals that macroH2A S-sulfhydration mediated by H2S in macrophages can alleviates liver injury in HFD-induced or CCl4-induced mice. Further, we identified key Cys286 of macroH2A as the specific S-sulfhydration residue (macroH2AC286-SSH). Mechanistically, genome-wide analyses demonstrate that macroH2AC286-SSH not only attenuates enhancer signals but also promotes chromatin compaction, thereby inhibiting macrophage-mediated inflammatory responses; in contrast, mutation at the Cys286 residue of macroH2A abolishes these effects. Collectively, our work elucidates the specific mechanism by which macroH2AC286-SSH regulates gene transcription in macrophages, and also establishes a significant role of macroH2AC286-SSH in the protective effects of H2S against liver injury, indicating that targeting macroH2A S-sulfhydration in macrophages represents a promising intervention for liver disease.