Jun modulates endoplasmic reticulum stress-associated ferroptosis in dorsal root ganglia neurons during neuropathic pain by regulating Timp1

• Published in: Neurochemistry international 2024-11, Vol.180, p.105877, Article 105877
• Main Authors: Lin, Ziqiang, Wang, Yi, Deng, Yingdong, Li, Lu, Cao, Yu, Wang, Suo, Zhang, Xiangsheng, Ding, Guoda, Cheng, Jiurong, Tang, Simin, Zhou, Jun
• Format: Article
• Language: English
• Subjects: Animals; Dorsal root ganglia; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; Ferroptosis; Ferroptosis - drug effects; Ferroptosis - physiology; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Jun; Male; Mice; Mice, Inbred C57BL; Neuralgia - metabolism; Neurons - metabolism; Neurons - pathology; Neuropathic pain; Proto-Oncogene Proteins c-jun - metabolism; Rats; Rats, Sprague-Dawley; Timp1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism
• ISSN: 0197-0186; 1872-9754; 1872-9754
• DOI: 10.1016/j.neuint.2024.105877

Neuropathic pain (NP) is a complex disorder caused by lesions or diseases affecting the somatosensory nervous system, severely impacting patients' quality of life. Recent studies suggest ferroptosis may be involved in NP induction, but its precise mechanisms remain unclear. We used GO and KEGG pathway enrichment analyses to functionally annotate ferroptosis-related differentially expressed genes (FRDs). Through STRING and the maximum cluster centrality (MCC) algorithm, we identified five hub FRDs (Jun, Timp1, Egfr, Cdkn1a, Cdkn2a). Single-cell analysis revealed significant expression of Jun and Timp1 in neurons. Our study confirmed the association between ferroptosis and endoplasmic reticulum stress (ERS) in NP and validated changes in hub FRD expression across various NP animal models. In vitro experiments demonstrated that Jun regulates neuronal ferroptosis and ERS, particularly by modulating Timp1 expression. Transcription factor prediction and JASPAR binding site analysis elucidated the regulatory network involving Jun. ROC curve analysis of external datasets highlighted the diagnostic potential of hub FRDs and ERS-related differentially expressed genes (ERSRDs) in NP. Using the Comparative Toxicogenomics Database (CTD), we identified estradiol (E2) as a potential therapeutic drug targeting hub FRDs and ERSRDs. Molecular docking predicted its binding sites with Jun and Timp1, and in vivo experiments confirmed that E2 alleviated NP and reversed the expression of Jun and Timp1. This study underscores the crucial role of Jun and Timp1 in the interplay between ferroptosis and ERS, offering new insights and promising avenues for NP treatment. •Jun regulates Timp1 to affect glutamate-induced neuronal ferroptosis.•ROC analysis validates diagnostic potential of ferroptosis & ER stress genes in NP.•Estradiol is a potential therapeutic for ferroptosis, offering a new treatment for NP.