The pivotal role and intervention strategies of BMAL1 mediated circadian clock dysregulation in intervertebral disc degeneration.

BACKGROUND

Intervertebral disc degeneration (IVDD), a primary cause of chronic low back pain, involves extracellular matrix (ECM) degradation and nucleus pulposus cell apoptosis. While traditionally linked to mechanical stress, inflammation, oxidative stress, and metabolic dysfunction, emerging evidence positions circadian clock disruption as the central hub integrating these factors. Under physiological conditions, the core clock genes BMAL1/CLOCK regulate ECM homeostasis.

RESULTS

In IVDD, however, this rhythm is disrupted: abnormal mechanical stress inhibits BMAL1 via the RhoA/ROCK pathway; inflammation (e.g., IL-1β) suppresses BMAL1 transcription through NF-κB, creating a vicious cycle; aging-related oxidative stress and ferroptosis are exacerbated by BMAL1 epigenetic silencing; and metabolic disorders promote NLRP3 inflammasome activation via mTORC1-mediated autophagy suppression and miR-155-dependent BMAL1 mRNA decay. Consequently, circadian dysregulation accelerates ECM breakdown and mitochondrial apoptosis. This synthesis establishes a novel 'circadian-centric' model of IVDD, unifying multifactorial pathogenesis under the framework of rhythm disruption. It reveals precise pathways such as RhoA/BMAL1/ECM, bridging key mechanistic gaps. Therapeutically, this model advocates a paradigm shift from symptomatic management to circadian rhythm reconstruction. Potential strategies include restoring BMAL1 rhythmicity to reverse ECM catabolism, targeting the circadian-inflammatory axis (e.g., melatonin, IL-1β antagonists) to concurrently mitigate inflammation and oxidative damage, and employing chrono-therapeutic interventions such as timed mechanical loading or nighttime drug administration.

CONCLUSION

This review provides a foundational rationale for developing chrono-precise diagnostics and treatments, aiming to redefine IVDD management toward endogenous rhythm restoration.