Abstract

Circadian rhythms are essential for maintaining intervertebral disc (IDD) homeostasis and regulate cellular metabolism, mechanical responses, and therapeutic efficacy. Core clock genes, especially CLOCK and BMAL1, have central roles in controlling energy metabolism, autophagy, and extracellular matrix production in disc cells. When circadian rhythms are disturbed, the progression of intervertebral disc degeneration (IDD) can be accelerated through increased inflammatory activity and impaired nutrient supply, which is particularly harmful in the avascular environment of the disc. Circadian regulation also influences how disc cells adapt to mechanical stress, thereby helping maintain disc structure and function under both normal and pathological loading conditions. As a result, people who are chronically affected by circadian disruption, such as shift workers or individuals with long-term sleep loss, may have a higher risk of developing IDD. From a therapeutic perspective, strategies based on circadian regulation, including light therapy, time-restricted feeding, and chronotherapy, have shown potential to slow or even reverse degenerative changes by re-establishing synchrony with endogenous biological rhythms. This review summarizes the role of circadian rhythms in IDD homeostasis and IDD progression, and further discusses the clinical significance of circadian-targeted approaches for the prevention and treatment of spinal disorders.

1 Introduction

Intervertebral disc degeneration (IDD) is a common pathological process underlying many spinal disorders and is closely associated with chronic low back pain, one of the leading causes of disability worldwide (GBD 2019 Diseases and Injuries Collaborators, 2020). With the progressive aging of the global population, the burden of IDD continues to increase. Imaging studies have shown that more than 90% of individuals over 65 years of age have varying degrees of disc degeneration (Mohd Isa et al., 2022). At the same time, IDD has shown a clear trend toward younger onset. MRI-based studies suggest that approximately 30%–50% of adults aged 30–50 years already present imaging features of intervertebral disc degeneration (Brinjikji et al., 2015). Structural damage caused by IDD can directly reduce spinal stability and lead to persistent pain, nerve compression, and functional impairment (Andersson, 1999). These clinical manifestations not only markedly affect quality of life, but also reduce work capacity and increase healthcare costs (Hoy et al., 2012).

IDD, located between adjacent vertebral bodies, serves as the functional joint of the spine and is composed of three main structures: the inner nucleus pulposus (NP), the surrounding annulus fibrosus (AF), and the upper and lower cartilaginous endplates (CEPs) (Peng et al., 2022). As a shock-absorbing structure, the IDD distributes mechanical loads and buffers axial stress (Mantha et al., 2019). Extracellular matrix imbalance is considered a major contributor to disc degeneration (Takeda et al., 2010). The NP is an avascular and highly hydrated tissue that maintains disc shape and function through regulation of extracellular matrix (ECM) homeostasis (Bian et al., 2017). The AF is a fibrocartilaginous structure located at the disc periphery, where it helps bear spinal loading and reduces pressure on the NP under physiological conditions (Holm et al., 1981). CEP cells, as part of the cartilage endplate, are responsible for nutrient transport and help maintain the avascular microenvironment of the disc (Deer et al., 2019). Current evidence suggests that aging, abnormal mechanical stress, and inflammation are all major factors involved in the pathogenesis of IDD degeneration.

Circadian rhythms are evolutionarily conserved regulatory systems that allow organisms to adapt continuously to environmental changes through coordinated control of multiple physiological processes (Patke et al., 2020). Increasing evidence shows that circadian rhythms play important roles in aging, stress responses, and inflammation (Deyurka et al., 2024). The suprachiasmatic nucleus (SCN) of the hypothalamus is widely regarded as the central pacemaker of the body, coordinating nutrient metabolism, energy balance, redox homeostasis, and behavioral activity through a 24-h oscillatory system (Hastings et al., 2018). Core clock genes, including CLOCK, BMAL1, PER, and CRY, are essential components of circadian regulation. Through a transcription-translation feedback loop (TTFL), the CLOCK/BMAL1 and PER/CRY complexes maintain circadian rhythms at the cellular and tissue levels (Takahashi, 2017) (Table 1).

Therapeutic strategyMechanismPotential impactApplication scenarioReferencesLight TherapyRestores circadian rhythms via the SCN.Reduces inflammation and slows degenerationFor high-risk groups with disrupted circadian rhythms (shift workers, jet lag)Touitou et al. (2016), Dibner et al. (2010)Timed FeedingAligns feeding with circadian timingEnhances autophagy and delays degenerationFor patients at risk of metabolic disorders or needing long-term nutritional interventionLai et al. (2023), Ma et al. (2022); Zhang et al. (2019)ChronotherapyTimes drug delivery to biological rhythmsImproves anti-inflammatory effects and repairFor patients requiring long-term treatment with minimal side effectsBaxter and Ray (2020),Lee et al. (2021b)Pharmacological InterventionRegulates clock genes linked to autophagy and inflammationEnhances autophagy and preserves matrix synthesisFor patients with circadian gene abnormalities or significant inflammationYu et al. (2021), Maiese (2017)Lifestyle ModificationImproves daily habits to maintain circadian balanceReduces degradation and supports repair.For preventive interventions in general populations at risk of circadian disruptionChappuis et al. (2013), Xing et al. (2021), Wang et al. (2021)Multi-Omics Research and Personalized TreatmentUses multi-omics to track circadian effects on disc healthIdentifies biomarkers for early diagnosisFor patients needing precision treatment and better response to therapiesGuo et al. (2023),Jordan and Lamia (2013), Mei et al. (2022)

Circadian regulation of intervertebral disc homeostasis and its therapeutic potential.

SCN, suprachiasmatic nucleus; IL-6, Interleukin 6; TGF-β, transforming growth factor beta; AMPK, AMP-Activated Protein Kinase; mTOR, mechanistic target of rapamycin; BMAL1, Brain and Muscle ARNT-Like 1; REV-ERBα, Nuclear Receptor Subfamily 1 Group D Member 1 (also known as NR1D1).

Recent studies have linked circadian rhythm disruption to the development of many chronic diseases, including metabolic syndrome, cardiovascular disease, and cancer (Scheiermann et al., 2013). In the intervertebral disc, circadian gene expression may influence tissue homeostasis by regulating cellular metabolism, matrix synthesis, and inflammatory responses. For example, inhibition of BMAL1 expression has been associated with metabolic imbalance in disc cells, nucleus pulposus cell dysfunction, and accelerated matrix degradation, while BMAL1-deficient mice develop features of IDD(17). These findings suggest that circadian rhythms may contribute to the maintenance of disc cell function and help delay or mitigate degenerative changes. Therefore, exploring the mechanisms and potential applications of circadian regulation in IDD is of clear scientific and clinical importance.

Current treatments for IDD mainly include conservative management and surgery. However, conservative therapies generally relieve symptoms without stopping or reversing degeneration (Santos et al., 2022). Surgical treatment may be necessary in selected cases, but its long-term efficacy is limited and it carries surgical risks and possible complications (Daly et al., 2016). For example, adjacent segment disease (ASD) may occur after spinal fusion (Aiki et al., 2005). For this reason, there is still an urgent need to develop new strategies that can effectively slow or reverse the progression of IDD.

As an intrinsic regulatory system that affects both systemic physiology and the molecular pathways involved in disc homeostasis, circadian rhythm has emerged as a promising target in IDD management. This review aims to summarize the relationship between circadian rhythms and intervertebral disc health, and to provide new perspectives for future research and clinical practice.

2 Molecular mechanisms of circadian rhythms

Circadian rhythms regulate a wide range of physiological processes in the human body and are mainly controlled by the coordinated action of core clock genes, including CLOCK (Circadian Locomotor Output Cycles Kaput), BMAL1 (Brain and Muscle ARNT-Like 1), PER (Period), and CRY (Cryptochrome), among which CLOCK and BMAL1 function as the main positive regulators. The CLOCK gene encodes the CLOCK protein, which forms a heterodimer with BMAL1 and acts as a transcriptional activator complex to drive downstream gene expression, with predominant activity during the night phase (Takahashi, 2017; Partch et al., 2014). This complex binds to E-box elements (CACGTG sequence) in target genes and promotes the expression of PER and CRY. After translation, PER and CRY proteins undergo phosphorylation by CK1ε/δ (casein kinase 1 ε/δ), enter the nucleus, and inhibit CLOCK/BMAL1 activity, thereby suppressing further PER and CRY transcription and forming a stable 24-h cycle (Partch et al., 2014; Qu et al., 2023). Phosphorylation of BMAL1 is an important regulatory step in this process, and CK1ε/δ contributes to this modification (Eide et al., 2005). CRY proteins suppress transcription mainly through direct interaction with the CLOCK/BMAL1 complex, especially via the PAS-B domain of BMAL1, and this process is further influenced by CRY phosphorylation and ubiquitination (Albrecht, 2012). CRY ubiquitination depends on FBXL3 (F-Box and Leucine-Rich Repeat Protein 3) and FBXL21 (F-Box and Leucine-Rich Repeat Protein 21), two ubiquitin ligases that regulate CRY stability and thereby influence circadian precision (Siepka et al., 2007). In addition, the nuclear localization signal (NLS) and nuclear export signal (NES) of PER proteins control their transport between the nucleus and cytoplasm, which is essential for accurate circadian timing (Hastings et al., 2018).

This interlocked transcription-translation feedback loop (TTFL) not only determines circadian oscillation itself, but also has important effects on cell metabolism and proliferation (Figure 1). For example, the CLOCK/BMAL1 complex can activate downstream genes together with transcription of Rev-erbα (Nr1d1) and Rorα (RORA), both of which are important in lipid metabolism and inflammatory regulation (Preitner et al., 2002; Solt et al., 2012). Some studies have shown that CLOCK deficiency or dysfunction can contribute to metabolic disorders such as obesity and type 2 diabetes (Rudic et al., 2004). In addition, Period2 (Per2) and BMAL1 have been shown to regulate autophagy-related genes, including mTORC1, Atp6v1d (ATPase H + -translocating lysosomal V1 subunit D), ATG4a, ATG4d, Beclin1, Bnip3, Ulk1a, and Ulk1b, thereby affecting autophagic flux (Huang et al., 2016; Wu et al., 2019; Kalfalah et al., 2016).

BMAL1 and CLOCK form heterodimers at night and bind to E-box elements to activate downstream genes involved in inflammatory regulation, lipid metabolism, gluconeogenesis, and mitochondrial and matrix metabolism. During the daytime phase, PER and CRY are activated, phosphorylated, and translocate into the nucleus, where they inhibit CLOCK/BMAL1 activity. This transcriptional-translational feedback loop maintains a stable 24-h circadian rhythm.

Circadian rhythms are centrally regulated by the suprachiasmatic nucleus (SCN) in the hypothalamus, while peripheral tissues are controlled by local clock genes expressed in peripheral cells. Representative tissues include the liver, muscle, and bone, where circadian regulation is closely linked to specific physiological functions (Gossan et al., 2013; Dudek et al., 2016). In the liver, circadian rhythms regulate glucose and lipid metabolism as well as the expression of detoxification enzymes.CLOCK/BMAL1 dimerization directly activates the expression of genes such as Pparα and Srebp1, which control several key steps in lipid metabolism (Balsalobre et al., 2000; Zhang et al., 2009). Circadian rhythms also influence gluconeogenesis and glucose output through regulation of genes such as G6pc and Pepck (Dyar et al., 2014). In intestinal epithelial cells, REV-ERBα and RORα help maintain intestinal homeostasis, and this regulatory effect can be strengthened through inhibition of the NF-κB/Nlrp3 inflammatory axis (Wang et al., 2018). In skeletal muscle, circadian rhythms are involved in energy metabolism and muscle repair. The CLOCK/BMAL1 complex affects mitochondrial biogenesis and energy metabolism through regulation of PGC-1α (Halling and Pilegaard, 2020). BMAL1-deficient mice show marked muscle atrophy and reduced strength, supporting an important role of circadian regulation in muscle maintenance (Ray et al., 2020). In addition, the mTOR pathway in muscle is also under circadian control, and BMAL1 can influence protein synthesis and muscle repair by regulating phosphorylation of S6K1 and 4E-BP1 (Lipton et al., 2015). In bone, circadian rhythms participate in bone formation and remodeling. The CLOCK/BMAL1 complex regulates the expression of RUNX2 and Osterix, thereby affecting osteoblast differentiation and function (Dudek et al., 2017). Circadian rhythms in bone also influence the RANKL/OPG system, which helps balance osteoclast activity and bone resorption and is therefore important for maintaining bone mass (Yang et al., 2016) (Table 2).

AspectMechanismReferencesKey Circadian MoleculesBMAL1: Regulates autophagy, metabolism, and inflammation, maintaining disc matrix homeostasis under stressTouitou et al. (2016), Yu et al. (2021), Maiese (2017), Wang and Griffith (2010)CLOCK: Partners with BMAL1, influencing circadian rhythm-dependent DNA repair in disc cellsTouitou et al. (2016), Dibner et al. (2010)PER1/PER2: Inhibit BMAL1/CLOCK and regulate matrix turnoverGuo et al. (2023),Jordan and Lamia (2013)REV-ERBα: Represses BMAL1 and modulates inflammation and metabolismYu et al. (2021), Békés et al. (2022), Mei et al., 2022)Pathways Affected by Circadian RhythmsAutophagy Pathway: BMAL1 regulates autophagy and limits disc cell senescenceMaiese (2017), Mei et al. (2022)Inflammation Pathway: Inflammation Pathway: Circadian control of NF-κB and IL-6/TNF-α modulates inflammation in disc tissueBaxter and Ray (2020),Zhang et al. (2022b)Metabolic Pathways (AMPK/mTOR): Controls energy balance and nutrient sensing in disc cellsLai et al. (2023), Zhang et al. (2019), Chappuis et al. (2013)Oxidative Stress Response: Circadian genes support antioxidant defense in disc cellsLee et al. (2021b), Jordan and Lamia (2013)Potential Therapeutic TargetsBMAL1 Activation: Enhances autophagy, reduces inflammation, and slows degenerationMaiese (2017)Xing et al. (2021)REV-ERBα Modulation: Targets REV-ERBα to reduce inflammation and stabilize the matrixYu et al. (2021), Mei et al. (2022), Békés et al. (2022)AMPK Activation: Enhances energy balance and autophagy, preserving disc cell functionLai et al. (2023), Zhang et al. (2019)SIRT1 Activation: Boosts autophagy and reduces oxidative stress, protecting disc cellsMa et al. (2022), Xing et al. (2021)Potential Therapeutic DrugsREV-ERBα Agonists: Regulate BMAL1 expression and inflammatory responses, with improved specificity and bioavailabilityYu et al. (2021), Békés et al. (2022)SIRT1 Activators: Promote autophagy and reduce oxidative damage, targeting disc cellsGuo et al. (2023),Xing et al. (2021)AMPK Activators: Enhance energy homeostasis and autophagy, slowing disc degenerationLai et al. (2023), Zhang et al. (2019)Corticosteroids (Timed): Administered with circadian rhythms to reduce inflammatory cytokines and protect the disc matrixBaxter and Ray (2020),Lee et al. (2021b), Zhang et al. (2022b)

Circadian molecules and signaling pathways involved in intervertebral disc health.

BMAL1, Brain and Muscle ARNT-Like 1; CLOCK, circadian locomotor output cycles kaput; PER1/PER2, Period Circadian Regulator 1/2; REV-ERBα, Nuclear Receptor Subfamily 1 Group D Member 1 (also known as NR1D1); NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; IL-6, Interleukin 6; TNF-α, tumor necrosis factor alpha; AMPK, AMP-Activated Protein Kinase; mTOR, mechanistic target of rapamycin; SIRT1, Sirtuin 1; HIF1α, Hypoxia-Inducible Factor 1-alpha.

Although studies on circadian rhythms in the intervertebral disc remain limited, current evidence suggests that disc cells also possess intrinsic circadian characteristics. Expression of CLOCK, BMAL1, PER, and CRY in disc tissue changes with circadian cycles and may regulate matrix metabolism and cell survival, thereby contributing to disc homeostasis (Schmitt et al., 2018; Li B. et al., 2023). For example, BMAL1 is expressed in disc-related cells and is involved in matrix regulation through effects on MMP (matrix metalloproteinase) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family genes (Chen et al., 2023). CLOCK expression is associated with disc cell proliferation and autophagy, and CLOCK dysfunction can reduce autophagy in nucleus pulposus cells and further accelerate IDD. BMAL1 deficiency can also increase expression of inflammatory mediators such as TNF-α and IL-1β, activate the NF-κB pathway, and aggravate disc degeneration, suggesting that circadian regulation in the intervertebral disc may influence tissue health partly through control of inflammatory signaling (Dudek et al., 2023).

3 Circadian rhythm disruption and IDD

Circadian rhythm disruption caused by shift work, recurrent jet lag, and sleep deprivation has increasingly been recognized as an important factor affecting disc health in recent years (Ding et al., 2021) (Figure 2a) Studies have shown that shift workers often develop marked circadian disturbance because of long-term exposure to artificial light and irregular sleep-wake schedules, resulting in abnormal expression of core clock genes such as CLOCK and BMAL1. This disturbance not only promotes disc matrix degradation through regulation of inflammatory genes, including IL-6 and TNF-α, but also interferes with cellular metabolism and impairs the proliferative and reparative capacity of disc cells (Dudek et al., 2017). A recent study further showed that shift workers exhibit reduced activity of the Nrf2 signaling pathway, which is important in the response to oxidative stress. Suppression of Nrf2 increases intracellular oxidative stress, induces early apoptosis of disc cells, and accelerates IDD progression (Kang et al., 2020).

The contribution of circadian rhythm disruption to disc degeneration. (a) Disordered sleep-wake patterns caused by shift work or insomnia may promote disc degeneration, including disc deformation and abnormal mechanical loading. (b) Degeneration-related changes in the disc microenvironment may lead to nucleus pulposus (NP) cell apoptosis, annulus fibrosus (AF) rupture, and loss of NP integrity. (c) Circadian disruption alters clock gene expression and affects pathways involving Nrf2, HIF-1α, FOXO3a, YAP/TAZ, and JNK/p38, while increasing inflammatory mediators such as IL-6 and TNF-α. These changes contribute to matrix breakdown, NP cell apoptosis, and reduced mechanical elasticity.

Frequent jet lag and chronic sleep loss are also important contributors to circadian disruption. These conditions can aggravate dysregulation of oxygen homeostasis in disc cells by affecting stabilization of HIF-1α (hypoxia-inducible factor-1α). Under normal conditions, HIF-1α helps protect disc cells by supporting their adaptation to the hypoxic environment. However, disruption of circadian rhythms suppresses HIF-1α expression, leading to reduced matrix synthesis, impaired autophagy, and ultimately faster progression of IDD (Suyama et al., 2016; Li et al., 2021). In addition, recent work has linked abnormal expression of PER1 and PER2 to IDD under circadian disruption. Dysregulation of these genes not only disturbs the metabolic rhythm of disc cells, but also promotes cellular senescence and matrix degradation through interference with FOXO3a-dependent antioxidant responses (Zhou et al., 2019).

Mechanical stress is a well-recognized factor in intervertebral disc degeneration, and recent studies suggest that circadian rhythms are important in shaping how disc cells respond to mechanical loading. Circadian genes appear to influence time-dependent responses to mechanical stress through regulation of the YAP/TAZ pathway (Zheng-Wei et al., 2023). During the daytime, YAP/TAZ activity is increased, which promotes matrix protein synthesis and cell proliferation and helps maintain disc elasticity under loading. At night, YAP/TAZ activity declines, allowing cells to enter a reparative state and reduce the cumulative mechanical injury generated during the day (Hu et al., 2024). Recent studies indicate that circadian disruption disturbs this finely balanced system. It has been reported that circadian rhythm disruption causes abnormal activation of the JNK and p38 MAPK pathways, both of which are important in stress responses induced by mechanical loading. Enhanced nocturnal activation of these pathways promotes apoptosis and matrix breakdown, thereby accelerating IDD (Cui et al., 2021) (Figure 2b). Further work has highlighted the role of TGF-β signaling in the interaction between circadian rhythms and mechanical stress. Under normal conditions, TGF-β protects the disc by promoting matrix synthesis and extracellular matrix repair, whereas circadian disturbance reduces the effectiveness of this pathway, weakens resistance to mechanical stress, and increases susceptibility to IDD (Morris et al., 2021).

In recent years, animal studies have provided additional insight into how circadian rhythm disruption contributes to IDD. Knockout and mutant models have made it possible to define the role of circadian genes in disc homeostasis more clearly. For example, BMAL1 knockout mice show obvious features of IDD, underscoring the key role of BMAL1 in circadian regulation and matrix metabolism (Wang et al., 2022). Likewise, deletion of REV-ERBα can trigger IDD, further supporting the importance of circadian regulation through autophagic and metabolic pathways (Zhou et al., 2024). Experimental disruption of circadian rhythms in animals has also yielded important findings. For instance, alternating light-dark cycles have been used to mimic the effects of shift work or recurrent jet lag, and these models show significantly aggravated disc degeneration. In such models, SIRT1 levels are markedly reduced, leading to impaired autophagy and disturbed cellular energy metabolism, which ultimately accelerates IDD (Hao et al., 2022). Together, these studies reveal the multiple ways in which circadian rhythm disruption contributes to IDD and provide a theoretical basis for the future development of circadian-based therapeutic strategies (Figure 2c).

4 Crosstalk between IDD and circadian rhythms

The intervertebral disc is mainly composed of the nucleus pulposus, annulus fibrosus, and cartilaginous endplates, and these structures are all essential for maintaining disc integrity and function. CLOCK, BMAL1, PER, and CRY are expressed in the different cell types that make up these structures, and their rhythmic expression is closely associated with cyclic regulation of matrix metabolism, autophagy, inflammatory responses, and nutrient transport. Together, these processes are important for preserving disc homeostasis (Figure 3).

Under stable circadian conditions, osteogenesis-related genes such as SOX9 and RUNX2, together with matrix synthesis-related genes such as ACAN and Col2a, help maintain extracellular matrix production. In contrast, matrix-degrading enzymes, including MMP9 and MMP13, promote matrix breakdown and accelerate IDD. A stable circadian rhythm is also essential for active cellular and nutrient metabolism. Under energy-deficient conditions, physiological autophagy is induced through the SIRT1/AMPK pathway to support normal metabolic needs. When circadian rhythms are disrupted, however, pathological autophagy may be activated through mTOR/RHEB, while the NF-κB inflammatory pathway is also stimulated. This leads to accumulation of inflammatory mediators such as TNF-α, IL-1β, and IL-6, resulting in abnormal cell proliferation, buildup of metabolic by-products, cellular senescence, cell death, and eventually IDD.

4.1 Matrix metabolism

Matrix components such as collagen and proteoglycans are essential for maintaining the structure and function of the intervertebral disc. Their synthesis and degradation are tightly regulated by circadian rhythms. The CLOCK/BMAL1 heterodimer coordinates matrix synthesis during the circadian cycle by regulating genes such as COL2A1 and ACAN (Sherratt et al., 2019). For example, BMAL1 has been shown to directly regulate the expression of aggrecan and collagen II in disc-related cells (Morris et al., 2021). Matrix synthesis is generally enhanced during the daytime, when mechanical loading increases, and this process depends in part on BMAL1-mediated activation of protein synthesis through the mTOR pathway, which helps maintain disc elasticity. At night, when mechanical loading decreases, circadian genes regulate matrix-degrading enzymes to promote matrix turnover and remodeling under lower mechanical stress (Ding et al., 2021). In annulus fibrosus cells, expression of CRY1 and CLOCK is closely related to cell proliferation and matrix metabolism. CRY1 can indirectly regulate MMP expression by inhibiting CLOCK/BMAL1 activity, thereby affecting matrix degradation in the annulus fibrosus (Patke et al., 2017; Yoshida et al., 2014). This mechanism is important for maintaining annulus fibrosus stability under daytime mechanical loading (Ray et al., 2020). In cartilage endplate cells, circadian gene expression is also closely related to bone metabolism and matrix synthesis. BMAL1 expression in the cartilage endplate is positively associated with osteogenic and chondrogenic genes such as RUNX2 and SOX9, suggesting that BMAL1 contributes to maintenance of both the disc and adjacent bone tissue through regulation of these genes (Delisle et al., 2021).

When circadian rhythms are disrupted, however, the normal rhythm of matrix synthesis may be disturbed, leading to accelerated matrix breakdown and disc degeneration. MMPs and their tissue inhibitors (TIMPs) are major regulators of disc matrix metabolism (Roberts et al., 2006). CLOCK/BMAL1 has been shown to control matrix degradation and remodeling during the circadian cycle through regulation of MMP-3 and MMP-13 expression (He et al., 2018). Under physiological conditions, MMP expression increases at night and contributes to matrix turnover, which is consistent with nocturnal repair and remodeling activity (Ding et al., 2021; Morris et al., 2021). In contrast, circadian disruption reduces disc tolerance to abnormal mechanical loading and increases expression of matrix-degrading enzymes such as MMP-3 and MMP-13, thereby accelerating matrix damage and annulus fibrosus injury (Albazal et al., 2021).

These findings highlight the importance of circadian regulation in maintaining disc structure and function through control of matrix metabolism.

4.2 Autophagy

Autophagy is the process by which cells remove damaged organelles and metabolic waste through the action of autophagy-related genes. It can be broadly divided into physiological autophagy and stress-induced autophagy (Barbosa et al., 2018). Almost all stressors that disturb cellular homeostasis can trigger autophagy. Physiological autophagy serves as a protective mechanism and plays an important role in maintaining cellular homeostasis and biosynthetic function (Chen et al., 2024). In contrast, stress-induced autophagy is more closely linked to aging, immune disorders, and neurodegenerative diseases (Klionsky et al., 2021). Current evidence suggests that disc autophagy is closely associated with circadian regulation and that formation of autophagic vacuoles is influenced by clock genes (Rabi et al., 2019; Ma et al., 2011). Clock genes have been shown to regulate autophagosome formation and degradation through control of autophagy-related genes, thereby enhancing nocturnal autophagic activity and facilitating waste clearance and delayed cellular aging (Oyama et al., 2021). Conversely, circadian disruption or PER2 mutation can impair autophagy and promote accumulation of metabolic waste, which may further aggravate ID (Zhang J. et al., 2022). These findings suggest that autophagy dysregulation, which is influenced by clock genes, is closely associated with nucleus pulposus degeneration and aging.

AMPK (adenosine monophosphate-activated protein kinase) and mTOR (mechanistic target of rapamycin) are two major pathways involved in autophagy regulation, and both are closely controlled by circadian rhythms. CLOCK and BMAL1 affect energy metabolism and cell survival in disc cells through genes associated with the AMPK and mTOR pathways (Li Z. et al., 2023). As a cellular energy sensor, AMPK is activated under energy-deficient conditions, where it promotes energy production and autophagy while suppressing protein synthesis. Circadian rhythms influence AMPK activity through regulation of SIRT1, thereby shaping metabolic rhythms in cells (Lai et al., 2023). BMAL1 has been reported to affect AMPK activity indirectly through SIRT1 expression, reducing energy expenditure and promoting autophagy during the night phase (Ma et al., 2022). By contrast, the mTOR pathway is activated under nutrient-rich and energy-sufficient conditions to promote protein synthesis and cell proliferation. CLOCK/BMAL1 regulates downstream targets of the mTOR pathway, such as RHEB and S6K1, thereby influencing disc cell proliferation and metabolic activity across the circadian cycle (Li et al., 2024). Disruption of circadian rhythms may cause overactivation of mTOR, leading to abnormal proliferation and premature senescence of disc cells. For example, BMAL1 in nucleus pulposus cells affects cell proliferation and metabolism through the mTOR pathway (Cao, 2018). Loss of BMAL1 can result in hyperactivation of mTOR, which drives uncontrolled proliferation and accelerates cellular senescence (Engin, 2017). Together, these findings suggest that circadian regulation of autophagy may help protect the disc from degeneration.

4.3 Inflammatory

Circadian genes are closely linked to inflammatory pathways, particularly in intervertebral disc cells, where they modulate the timing and magnitude of inflammatory responses through regulation of inflammation-related genes. BMAL1, for example, plays an important role in suppressing NF-κB signaling (Dudek et al., 2017). NF-κB is a key transcription factor involved in expression of inflammatory mediators such as TNF-α and IL-1β, both of which contribute to IDD (Zhang et al., 2021; Dong et al., 2019). Under normal circadian conditions, BMAL1 directly or indirectly limits NF-κB activity and thereby reduces inflammatory mediator production. When circadian rhythms are disrupted, such as under sleep deprivation or clock gene mutation, this inhibitory effect is weakened, leading to a stronger inflammatory response, increased matrix degradation, and faster disc degeneration. In addition, CLOCK also participates in inflammatory regulation within the disc through effects on IL-6 and IL-1β expression (Dudek et al., 2017). Abnormal CLOCK activity can therefore lead to dysregulated release of inflammatory mediators and aggravate disc inflammation and degeneration.

The strength and duration of inflammatory responses are clearly influenced by circadian timing (Man et al., 2021). Studies have shown that inflammation in intervertebral disc tissue follows an obvious circadian pattern, with inflammatory mediator expression and release often peaking at night in parallel with systemic immune rhythms (Peng et al., 2022). Disturbance of circadian rhythms or mutation of clock genes can disrupt this temporal control and lead to inappropriate overexpression of inflammatory factors. For example, mice with circadian gene mutations show stronger inflammatory responses and more severe IDD in experimental models (Suyama et al., 2016; Morris et al., 2021). These findings emphasize that intact circadian regulation is important for controlling inflammation in the disc and slowing degenerative progression.

4.4 Hemodynamics

As an avascular tissue, the intervertebral disc depends mainly on diffusion and osmotic processes for nutrient supply. Studies suggest that circadian rhythms influence nutrient delivery and waste clearance around the disc by regulating blood flow, osmotic pressure, and local cellular metabolic activity (Morris et al., 2021). Circadian activity in nucleus pulposus and annulus fibrosus cells affects diffusion and distribution of oxygen, glucose, and amino acids within the matrix. During the day, cellular activity is higher and metabolic demand increases, which is accompanied by greater demand for oxygen and nutrient supply within the disc. At night, metabolic demand decreases and changes in osmotic pressure help facilitate removal of waste products (Zhang et al., 2020). Circadian disruption may disturb this balance and contribute to IDD by impairing nutrient delivery. For example, chronic circadian disturbance can reduce oxygen and nutrient availability within the disc, leading to accumulation of metabolic byproducts, cell death, and matrix degradation. It has also been reported that circadian disruption