Abstract：
This study explores the molecular underpinnings of neuropathic pain (NPP) and neuroinflammation, focusing on the role of TRIM28 in the regulation of autophagy and microglia ferroptosis. Leveraging transcriptomic data associated with NPP, we identified TRIM28 as a critical regulator of ferroptosis. Through comprehensive analysis, including Gene Ontology enrichment and protein-protein interaction network assessments, we unveiled GSK3B as a downstream target of TRIM28. Experimental validation confirmed the capacity of TRIM28 to suppress GSK3B expression and attenuate autophagic processes in microglia. We probed the consequences of autophagy and ferroptosis on microglia physiology, iron homeostasis, oxidative stress, and the release of proinflammatory cytokines. In a murine model, we validated the pivotal role of TRIM28 in NPP and neuroinflammation. Our analysis identified 20 ferroptosis regulatory factors associated with NPP, with TRIM28 emerging as a central orchestrator. Experimental evidence affirmed that TRIM28 governs microglial iron homeostasis and cell fate by downregulating GSK3B expression and modulating autophagy. Notably, autophagy was found to influence oxidative stress and proinflammatory cytokine release through the iron metabolism pathway, ultimately fueling neuroinflammation. In vivo experiments provided conclusive evidence of TRIM28-mediated pathways contributing to heightened pain sensitivity in neuroinflammatory states. The effect of TRIM28 on autophagy and microglia ferroptosis drives NPP and neuroinflammation. These findings offer promising avenues for identifying novel therapeutic targets to manage NPP and neuroinflammation.
摘要：
这项研究探讨了神经性疼痛（NPP）和神经炎症的分子基础，重点研究TRIM28在调节自噬和小胶质细胞铁性凋亡中的作用。利用与NPP相关的转录组数据，我们确定TRIM28是铁凋亡的关键调节因子。通过综合分析,包括基因本体富集和蛋白质-蛋白质相互作用网络评估，我们公布了GSK3B作为TRIM28的下游目标。实验验证证实了TRIM28在小胶质细胞中抑制GSK3B表达和减弱自噬过程的能力。我们探讨了自噬和铁凋亡对小胶质细胞生理的影响，铁稳态，氧化应激，和促炎细胞因子的释放。在一个鼠类模型中，我们验证了TRIM28在NPP和神经炎症中的关键作用。我们的分析确定了20个与NPP相关的铁凋亡调节因子，随着TRIM28成为中央协调人。实验证据证实，TRIM28通过下调GSK3B表达和调节自噬来控制小胶质细胞铁稳态和细胞命运。值得注意的是,自噬通过铁代谢途径影响氧化应激和促炎细胞因子的释放,最终助长神经炎症。体内实验提供了TRIM28介导的途径有助于提高神经炎性状态的疼痛敏感性的确凿证据。TRIM28对自噬和小胶质细胞铁性凋亡的影响驱动NPP和神经炎症。这些发现为确定新的治疗靶标以管理NPP和神经炎症提供了有希望的途径。
