Protein SUMOylation is crucial in both physiological and pathological contexts, but its role in acute liver injury is poorly understood. We found that SENP3, a SUMO2/3 protease, rapidly accumulates in hepatocytes around the pericentral vein zone within 2 hours of CCl₄-induced liver injury in mice. Knockout of SENP3 in hepatocytes worsens liver damage and promotes pyroptosis. The project demonstrated that SENP3 inhibits hepatocyte pyroptosis through a finely tuned mechanism involving post-translational modifications and the stabilization of key biomolecules HNRNPL.