Xiong Xinyuan, Zhi Yang, Yang Nan, Zhao Wenzhen, Wang Shu, Zhu Huiqin, Tang Jieting, Yi Jing, Sun Xuxu, Yang Jie
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.
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.
iScience. 2025 Jul 7;28(8):113067. doi: 10.1016/j.isci.2025.113067. eCollection 2025 Aug 15.
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 (CCl)-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.
蛋白质SUMO化修饰在生理和病理情况下都至关重要，但其在急性肝损伤（ALI）中的作用尚不清楚。我们发现，SUMO2/3蛋白酶SENP3在小鼠四氯化碳（CCl）诱导的肝损伤后2小时内迅速在中央静脉周围区域的肝细胞中积累。肝细胞中SENP3基因敲除会加重肝损伤并促进细胞焦亡。机制上，SENP3与RNA结合蛋白HNRNPL相互作用，促进其去SUMO化修饰和蛋白酶体降解。HNRNPL的减少降低了核旁斑组装转录本1（Neat1）的水平，损害了其激活半胱天冬酶-1和诱导细胞焦亡的能力。此外，在药物性ALI患者中，SENP3和HNRNPL的水平均与细胞焦亡密切相关。总之，SENP3-HNRNPL-Neat1轴作为一种快速应激传感器，可减轻ALI期间过度的细胞焦亡，使SENP3和HNRNPL成为有前景的治疗靶点。
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