2. Academic Validation
  3. SENP3 protects hepatocyte from pyroptosis during acute liver injury through deSUMOylation of HNRNPL

SENP3 protects hepatocyte from pyroptosis during acute liver injury through deSUMOylation of HNRNPL

  • iScience. 2025 Jul 7;28(8):113067. doi: 10.1016/j.isci.2025.113067.
Xinyuan Xiong 1,  Yang Zhi 2,  Nan Yang 1,  Wenzhen Zhao 1 3,  Shu Wang 1,  Huiqin Zhu 1,  Jieting Tang 2,  Jing Yi 1,  Xuxu Sun 1,  Jie Yang 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China.
  • 3 Department of Histology and Embryology, School of Basic Medical Science, Dali University, Dali, China.
PMID: 40792025 DOI: 10.1016/j.isci.2025.113067
Abstract

Protein SUMOylation is crucial in both physiological and pathological contexts, but its role in acute liver injury (ALI) is poorly understood. We found that SENP3, a SUMO2/3 protease, rapidly accumulates in hepatocytes around the pericentral vein zone within 2 h of carbon tetrachloride (CCl4)-induced liver injury in mice. Knockout of SENP3 in hepatocytes worsens liver damage and promotes Pyroptosis. Mechanistically, SENP3 interacts with the RNA-binding protein HNRNPL, facilitating its deSUMOylation and proteasomal degradation. This reduction of HNRNPL decreases nuclear paraspeckle assembly transcript 1 (Neat1) levels, impairing its ability to activate Caspase-1 and induce Pyroptosis. Moreover, in patients with drug-induced ALI, the levels of both SENP3 and HNRNPL are strongly correlated with Pyroptosis. In conclusion, the SENP3-HNRNPL-Neat1 axis functions as a rapid stress sensor to mitigate excessive Pyroptosis during ALI, making SENP3 and HNRNPL promising therapeutic targets.

Keywords

Integrative aspects of cell biology; Molecular mechanism of gene regulation; Molecular network.

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