Bromodomain-containing protein 4 contributes to chronic postsurgical pain via activating TLR4/NF-kappaB-dependent neuroinflammation
Abstract Background Chronic pain affects 1.5 billion individuals worldwide but remains woefully undertreated, particularly occurring in the populations undergoing surgical procedures. Increasing evidence indicates that epigenetic modifications are involved in the pathogenesis of chronic pain. This s...
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BMC
2025-07-01
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| Series: | BMC Anesthesiology |
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| Online Access: | https://doi.org/10.1186/s12871-025-03216-6 |
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| author | Ruichen Shu Yuan Li Zengli Zhang Xuan Zhang Shan Guan Kaiyuan Wang Yiqing Yin |
| author_facet | Ruichen Shu Yuan Li Zengli Zhang Xuan Zhang Shan Guan Kaiyuan Wang Yiqing Yin |
| author_sort | Ruichen Shu |
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| description | Abstract Background Chronic pain affects 1.5 billion individuals worldwide but remains woefully undertreated, particularly occurring in the populations undergoing surgical procedures. Increasing evidence indicates that epigenetic modifications are involved in the pathogenesis of chronic pain. This study aimed to investigate the role of bromodomain-containing protein 4 (Brd4) in chronification of pain after surgery. Methods Male Sprague-Dawley rats were subjected to skin/muscle incision and retraction surgery to induce chronic postsurgical pain. Nociceptive thresholds and locomotor activity were assessed. The spinal cord was collected to detect the expressions of Brd4, toll-like receptor 4 (TLR4)/nuclear factor-kappaB (NF-κB) pathway, and proinflammatory cytokines and chemokines release. The BET inhibitor JQ1 was used to verify the contribution of Brd4 to chronic postsurgical pain. Results Significant upregulation of spinal Brd4 expression, accompanied by activation of the TLR4/NF-κB signaling cascade and increased release of proinflammatory mediators were presented in the rat model of chronic postsurgical pain. The BET inhibitor JQ1 prevented the development of chronic postsurgical pain in a dose-dependent manner. Moreover, JQ1 obviously suppressed the activation of TLR4 and the phosphorylation and translocation of NF-κB as well as subsequently cytokines and chemokines release, including IL-1β, IL-6, TNF-α, CXCL1, CXCL2 and CCL2. Conclusions The epigenetic regulator Brd4 initiates neuroinflammation in spinal cord through activating TLR4/NF-κB signaling pathway and enhancing cytokine and chemokines release, thereby contributing to the transition to chronic postsurgical pain. JQ1 halts chronic pain development, providing a novel therapy for patients at high risk of persistent pain. |
| format | Article |
| id | doaj-art-0e14d6cdb6d546d2baee7b149b29c410 |
| institution | Kabale University |
| issn | 1471-2253 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | BMC Anesthesiology |
| spelling | doaj-art-0e14d6cdb6d546d2baee7b149b29c4102025-08-20T04:02:55ZengBMCBMC Anesthesiology1471-22532025-07-0125111010.1186/s12871-025-03216-6Bromodomain-containing protein 4 contributes to chronic postsurgical pain via activating TLR4/NF-kappaB-dependent neuroinflammationRuichen Shu0Yuan Li1Zengli Zhang2Xuan Zhang3Shan Guan4Kaiyuan Wang5Yiqing Yin6Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineDepartment of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational MedicineAbstract Background Chronic pain affects 1.5 billion individuals worldwide but remains woefully undertreated, particularly occurring in the populations undergoing surgical procedures. Increasing evidence indicates that epigenetic modifications are involved in the pathogenesis of chronic pain. This study aimed to investigate the role of bromodomain-containing protein 4 (Brd4) in chronification of pain after surgery. Methods Male Sprague-Dawley rats were subjected to skin/muscle incision and retraction surgery to induce chronic postsurgical pain. Nociceptive thresholds and locomotor activity were assessed. The spinal cord was collected to detect the expressions of Brd4, toll-like receptor 4 (TLR4)/nuclear factor-kappaB (NF-κB) pathway, and proinflammatory cytokines and chemokines release. The BET inhibitor JQ1 was used to verify the contribution of Brd4 to chronic postsurgical pain. Results Significant upregulation of spinal Brd4 expression, accompanied by activation of the TLR4/NF-κB signaling cascade and increased release of proinflammatory mediators were presented in the rat model of chronic postsurgical pain. The BET inhibitor JQ1 prevented the development of chronic postsurgical pain in a dose-dependent manner. Moreover, JQ1 obviously suppressed the activation of TLR4 and the phosphorylation and translocation of NF-κB as well as subsequently cytokines and chemokines release, including IL-1β, IL-6, TNF-α, CXCL1, CXCL2 and CCL2. Conclusions The epigenetic regulator Brd4 initiates neuroinflammation in spinal cord through activating TLR4/NF-κB signaling pathway and enhancing cytokine and chemokines release, thereby contributing to the transition to chronic postsurgical pain. JQ1 halts chronic pain development, providing a novel therapy for patients at high risk of persistent pain.https://doi.org/10.1186/s12871-025-03216-6Chronic postsurgical painBrd4EpigeneticsNeuroinflammationNF-κB |
| spellingShingle | Ruichen Shu Yuan Li Zengli Zhang Xuan Zhang Shan Guan Kaiyuan Wang Yiqing Yin Bromodomain-containing protein 4 contributes to chronic postsurgical pain via activating TLR4/NF-kappaB-dependent neuroinflammation BMC Anesthesiology Chronic postsurgical pain Brd4 Epigenetics Neuroinflammation NF-κB |
| title | Bromodomain-containing protein 4 contributes to chronic postsurgical pain via activating TLR4/NF-kappaB-dependent neuroinflammation |
| title_full | Bromodomain-containing protein 4 contributes to chronic postsurgical pain via activating TLR4/NF-kappaB-dependent neuroinflammation |
| title_fullStr | Bromodomain-containing protein 4 contributes to chronic postsurgical pain via activating TLR4/NF-kappaB-dependent neuroinflammation |
| title_full_unstemmed | Bromodomain-containing protein 4 contributes to chronic postsurgical pain via activating TLR4/NF-kappaB-dependent neuroinflammation |
| title_short | Bromodomain-containing protein 4 contributes to chronic postsurgical pain via activating TLR4/NF-kappaB-dependent neuroinflammation |
| title_sort | bromodomain containing protein 4 contributes to chronic postsurgical pain via activating tlr4 nf kappab dependent neuroinflammation |
| topic | Chronic postsurgical pain Brd4 Epigenetics Neuroinflammation NF-κB |
| url | https://doi.org/10.1186/s12871-025-03216-6 |
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