Lin Yu, Chen Qiyong, Liu Shaoqiang, Liu Boling
Department of Spine Surgery, Fuzhou Second General Hospital, 47 Shangteng Road, Cangshan District, Fuzhou, 350007, China.
The Third Clinical Medical College, Fujian Medical University, Fuzhou, 350007, China.
Sci Rep. 2025 Apr 17;15(1):13280. doi: 10.1038/s41598-025-98283-7.
This study aimed to elucidate the cellular and molecular mechanisms of GSDME in GSDMD independent nucleus pulposus (NP) cell pyroptosis. We analyzed microarray datasets to identify differentially expressed genes (DEGs) in the progression of intervertebral disc degeneration (IDD) and conducted Gene Ontology analysis to elucidate DEGs-participated biological processes. We utilized lipopolysaccharides (LPS) to treat human primary NP cells to establish pyroptosis cell model. And siRNA was used to simulate a GSDMD-deficient environment. We used several regulators to figure out how GSDME was participate in pyroptosis via a GSDMD independent pathway. The molecular docking was conducted to identify compound that could possibly bind to GSDME and suppress its cleavage. Finally, Ocifisertib was intraperitoneally administered into IDD rat model to explore its therapeutic potential. Pyroptosis was activated in IDD. In vitro, LPS induced NP cell pyroptosis by promoting the cleavage of GSDMD and GSDME. In the absence of GSDMD, the cleavage of GSDME compensatively upregulated to mediate pyroptosis. Ocifisertib alleviated pyroptosis-mediated IDD by inhibiting GSDME cleavage in annulus fibrosus puncture-induced IDD rat model. Our study provides evidence that the cleavage of GSDME aggravates IDD by accelerating NP cell pyroptosis and demonstrates that Ocifisertib has therapeutic potential in IDD treatment.
本研究旨在阐明Gasdermin E（GSDME）在不依赖Gasdermin D（GSDMD）的髓核（NP）细胞焦亡中的细胞和分子机制。我们分析了基因芯片数据集，以鉴定椎间盘退变（IDD）进展过程中的差异表达基因（DEG），并进行基因本体分析以阐明DEG参与的生物学过程。我们利用脂多糖（LPS）处理人原代NP细胞以建立焦亡细胞模型。并使用小干扰RNA（siRNA）模拟GSDMD缺陷环境。我们使用了几种调节剂来弄清楚GSDME如何通过不依赖GSDMD的途径参与焦亡。进行分子对接以鉴定可能与GSDME结合并抑制其裂解的化合物。最后，将奥西福替布腹腔注射到IDD大鼠模型中以探索其治疗潜力。焦亡在IDD中被激活。在体外LPS通过促进GSDMD和GSDME的裂解诱导NP细胞焦亡。在没有GSDMD的情况下，GSDME的裂解代偿性上调以介导焦亡。在纤维环穿刺诱导的IDD大鼠模型中，奥西福替布通过抑制GSDME裂解减轻了焦亡介导的IDD。我们的研究提供了证据，证明GSDME的裂解通过加速NP细胞焦亡加重IDD，并证明奥西福替布在IDD治疗中具有治疗潜力。
