Melatonin mitigates intervertebral disc degeneration by suppressing NLRP3 inflammasome activation via the EGR1/DDX3X pathway

• Published in: The FASEB journal 2024-12, Vol.38 (24), p.e70143-n/a
• Main Authors: Zhao, Kangcheng, Zhang, Yukun, Liao, Zhiwei, Zhang, Weifeng, Li, Gaocai, Shi, Pengzhi, Cheng, Zhangrong, Chen, Yuhang, Li, Shuai, Wang, Kun, Song, Yu, Feng, Xiaobo, An, Ran, Yang, Cao
• Format: Article
• Language: English
• Subjects: Adult; Animals; DDX3X; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; EGR1; Female; Humans; Inflammasomes - metabolism; intervertebral disc degeneration; Intervertebral Disc Degeneration - drug therapy; Intervertebral Disc Degeneration - metabolism; Intervertebral Disc Degeneration - pathology; Male; melatonin; Melatonin - pharmacology; Middle Aged; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; nucleus pulposus; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202302453RRR

Intervertebral disc degeneration (IVDD), is one of the leading causes of low back pain. Inflammation is considered to be the main pathophysiological process of IVDD. The nucleotide‐binding domain and leucine‐rich pyrin domain containing 3 (NLRP3) inflammasome‐mediated inflammatory responses are critically involved in the progression of IVDD. Melatonin is known for its anti‐inflammatory and antioxidant effects. However, little is known about the potential effects of melatonin in the pathological process of IVDD. We found that the expression of EGR1, DDX3X, and NLRP3 inflammasome increased and extracellular matrix (ECM) degraded in IVDD. With the application of EGR1 siRNA, the expression of DDX3X and the activation of NLRP3 inflammasome were inhibited in stress‐induced NP cells. DDX3X/NLRP3 was regulated on dependence of EGR1. Besides, the utility of melatonin mitigated the EGR1‐induced overproduction of DDX3X and activation of NLRP3 inflammasome, thus protecting cells from pyroptosis and ECM degradation. In vivo, in a rat IVDD model, melatonin was found to be able to delay the development of IVDD by imageological and histological evaluation. In conclusion, our study demonstrated that melatonin prevented IVDD progression by regulating EGR1/DDX3X/NLRP3 axis. Our study provides insight into melatonin as a new target for therapeutic approaches for IVDD. Mechanical stress is an important cause of intervertebral disc degeneration. Mechanical stress was found to induce the expression of DDX3X by EGR1. DDX3X is a key factor in NLRP3 inflammasome activation. Activated NLRP3 inflammasome cleave GSDMD and IL‐1β precursors into active GSDMD‐N and IL‐1β, intensifying inflammatory response. Melatonin was found to inhibit inflammatory response induced by DDX3X via inhibiting EGR1 expression. This paper explores a new mechanism for melatonin to alleviate intervertebral disc degeneration.