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Adapt, Mitigate, and Target: The Role of Oxidative Stress in Intervertebral Disc Homeostasis and Disc Degeneration

Shota Tamagawa1,2,*orcid, Jordy Schol3,4,*orcid, Luca Ambrosio3,5,6orcid, Hidetoshi Nojiri1,2, Muneaki Ishijima1,2, Daisuke Sakai3,4orcid
Neurospine 2026;23(2):316-334.
Published online: April 30, 2026

1Department of Orthopaedics, Juntendo University Faculty of Medicine, Tokyo, Japan

2Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Department of Orthopaedic Surgery, Tokai University School of Medicine, Isehara, Japan

4Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan

5Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy

6Research Unit of Orthopaedic and Trauma Surgery, Departmental Faculty of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy

Corresponding Author Daisuke Sakai Tokai University School of Medicine, Department of Orthopedic Surgery, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan Email: daisakai@tokai.ac.jp

Shota Tamagawa and Jordy Schol contributed equally to this study as co-first authors.

• Received: February 20, 2026   • Revised: March 9, 2026   • Accepted: March 11, 2026

Copyright © 2026 by the Korean Spinal Neurosurgery Society

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • The intervertebral disc (IVD) is defined by a uniquely avascular niche characterized by constitutive hypoxia, limited nutrient diffusion, acidic pH, hyperosmolarity, and repetitive mechanical loading. These stressors interact with each other rather than acting in isolation. Reduced endplate transport exacerbates hypoxia and glucose deprivation, driving glycolytic lactate accumulation and acidification. In parallel, acid-osmotic stress perturbs ion homeostasis and mitochondrial membrane potential, while mechanical loading promotes microdamage and inflammatory mediator release. Together they converge on common reactive oxygen species (ROS)-generating nodes, including mitochondrial electron transport disruption, membrane oxidase activation, and endoplasmic reticulum stress, while redox-sensitive signaling by nuclear factor erythroid 2-related factor 2, hypoxia-inducible factor 1/2, nuclear factor kappa B, and mitogen-activated protein kinases integrates metabolic rewiring with catabolic and inflammatory programs. In a healthy state, controlled ROS levels participate in healthy cell signaling and are counterbalanced by antioxidant systems; however, when compensatory capacity is exceeded, oxidative stress becomes self-reinforcing through inflammation-ROS feedback, mitochondrial dysfunction, and impaired proteostasis. This shift drives apoptosis and senescence of disc cells, extracellular breakdown, and endplate, thereby promoting IVD degeneration and creating a microenvironment for vascular and nerve ingrowth associated with discogenic low back pain. We propose an “Adapt-Mitigate-Target” framework that maps (1) physiological adaptation, (2) transition to redox breakdown, and (3) therapeutic opportunities to reduce the oxidative stress burden. We also highlight translational constraints imposed by disc transport barriers and discuss stage-appropriate systemic, local/intradiscal, and mitochondria-directed strategies, alongside a roadmap for biomarkers, precision phenotyping, and combination therapies.
  • Keywords: Oxidative stress, Redox homeostasis, Intervertebral disc, Low back pain, Cellular senescence, Inflammation
The intervertebral disc (IVD) constitutes a demanding niche shaped by substantial multidirectional mechanical loads, limited vascular supply, and strict metabolic constraints. Its extracellular matrix (ECM) and cell populations create a specialized tissue that relies on a finely regulated biochemical equilibrium. The nucleus pulposus (NP), rich in proteoglycans and type II collagen, forms the hydrated core, while the cartilaginous endplates (CEP) form the interface with the vertebral bodies and act as the primary route for IVD nutrient delivery and waste removal. Together with the annulus fibrosus (AF), these regions support continuous matrix synthesis and provide the disc with its biomechanical capacities. Because solute movement within the disc relies entirely on slow diffusion, the internal environment becomes chronically hypoxic, acidic, hyperosmolar, and poor in glucose [1,2]. Disc cells must therefore employ a series of specialized adaptations to sustain viability and preserve tissue function within these constraints.
The IVD becomes progressively more vulnerable as age, lifestyle factors, genetic predisposition, and mechanical insults accumulate. These influences destabilize the disc’s biochemical and biomechanical balance and impair the activity of resident cells, reducing their ability to maintain the ECM that supports its load-bearing function [3]. As ECM turnover falters, the NP loses full-length proteoglycans and shifts from type II to type I collagen, weakening swelling capacity and mechanical resilience [3]. Cellular stress also promotes inflammatory and catabolic signaling that accelerates ECM breakdown. In parallel, oxidative stress (OS), defined as an imbalance among reactive oxygen species (ROS) accumulation and antioxidant defenses, has emerged as a central driver of degeneration [4]. Excess ROS impair mitochondrial function, induce cell senescence, promote DNA damage, disrupt anabolic pathways, and amplify inflammation [5,6]. When antioxidant systems are overwhelmed, oxidative damage reinforces this degenerative cycle. Progressive loss of structural integrity is compounded by the disc’s minimal vascularity and limited progenitor pool [7,8], ultimately allowing AF or CEP damage to expose the NP to the systemic environment, thereby potentially triggering immune infiltration, neural ingrowth, and aberrant vascularization. Collectively, these events often culminate in the onset of discogenic low back pain (LBP) [9], which is closely associated with IVD degeneration (IDD), and constitutes the leading cause of disability worldwide.
Clinical studies report that patients with disc herniation or chronic LBP show elevated systemic markers of oxidative damage, though these studies show mixed correlation with pain intensity [10,11]. Experimental models further demonstrate that excess ROS accelerate NP cell senescence, impair mitochondrial function, and disrupt ECM homeostasis, collectively driving progressive degeneration. As inflammation, metabolic strain, and redox imbalance converge within the disc microenvironment, OS provides a plausible mechanistic link among cellular dysfunction, ECM breakdown, and the onset of painful symptoms [12]. Given this growing evidence implicating OS in IDD, combined with the expected increase in LBP with increments of life expectancy, diabetes, and obesity, it is critical to understand how redox imbalance interacts with the unique disc niche and to explore whether these pathways offer therapeutic targets [13,14]. Several recent reviews have comprehensively summarized immunometabolic and degenerative pathways in IDD; in contrast, this narrative review is organized around a clinically actionable redox trajectory that is explicitly compartment- and stage-aware. This review aims to synthesize current evidence into a practical framework that (1) delineates how NP, AF, and CEP cells adapt to coupled microenvironmental stressors, (2) defines where and why these adaptations cross a redox threshold into self-amplifying oxidative distress, and (3) translates this transition into testable, stage- and cell-type–matched hypotheses for therapeutic prioritization and biomarker-guided patient stratification. Accordingly, we propose the “Adapt-Mitigate-Target” framework as a predictive schema to inform trial design and accelerate translation (Fig. 1).
We conducted a narrative literature review of OS and redox regulation in IVD homeostasis and degeneration. We searched PubMed/MEDLINE (final search: December 16, 2025) using combinations of key terms related to (1) disc and cell types (“intervertebral disc,” “nucleus pulposus,” “annulus fibrosus,” “cartilaginous endplate”), and (2) OS and redox biology (“oxidative stress,” “reactive oxygen species,” “redox,” “mitochondria,” “senescence,” “inflammation”). We prioritized primary research articles and recent reviews published in English, and selected studies to represent key mechanisms and therapeutic strategies across disc compartments and disease stages. To provide an evidence overview, we categorized the included intervention studies by evidence tier: in vitro, in vivo preclinical, human observational, and human interventional. Evidence tier and translation status are summarized in Table 1. As this is a narrative rather than a systematic review, the synthesis is not exhaustive and may be subject to selection and publication bias.
OS is universally recognized as a critical contributor to numerous pathologies, including cardiovascular, neurodegenerative, and musculoskeletal diseases. Fundamentally, OS is defined as an imbalance between oxidants and antioxidants in favor of the oxidants, resulting in the disruption of redox signaling and molecular damage (Fig. 2A) [15].
1. Mechanisms of Oxidative Damage
ROS are highly reactive oxygen-containing molecules generated as natural byproducts of cellular metabolism. Key ROS include the free radicals superoxide anion (O2·−) and hydroxyl radical (·OH), as well as non-radical molecules like hydrogen peroxide (H2O2) [16]. Endogenous ROS sources primarily originate from mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and the cytochrome P450 enzyme systems. ROS exist along a spectrum of biological activity. “Oxidative eustress” refers to low to mild levels of oxidants that participate in physiological redox signaling and regulate key pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). Conversely, “oxidative distress” occurs when ROS generation exceeds the tissue’s antioxidant capacity, causing damage to essential cellular components, including lipids, proteins, and DNA. This leads to mitochondrial dysfunction, cellular senescence, inflammatory phenotypes, and matrix catabolism, which may promote the activation of cell death pathways such as apoptosis, necroptosis, pyroptosis, and ferroptosis; all hallmarks of IDD [3]. To operationalize this continuum in the IVD, we define a “redox threshold” as the tipping point at which ROS production and oxidant burden exceed the combined capacity of antioxidant buffering, proteostasis, and organelle quality control, switching ROS from adaptive signaling to self-amplifying damage. Beyond this threshold, feed-forward loops emerge, locking disc cells into catabolic, senescent, and death-prone states (Fig. 2B). This concept has direct therapeutic implications. Indiscriminate scavenging of all ROS may blunt essential eustress signaling and impair repair, whereas stage-appropriate interventions should aim to restore redox balance and interrupt amplification loops rather than eliminate ROS outright [17]. Importantly, the redox threshold is not uniform across disc compartments. NP cells are conditioned to tolerate hypoxia-associated ROS through constitutive hypoxia-inducible factor (HIF) programs and specialized mitochondrial adaptations, AF cells are more load-responsive to mechanotransductive ROS, and CEP cells are particularly vulnerable to iron-dependent lipid peroxidation and ferroptosis. This compartmental heterogeneity supports stage- and cell-type–matched therapeutic strategies and biomarker selection. Practical proxy categories for identifying a ‘redox threshold’ include oxidative damage markers (e.g., lipid peroxidation and oxidative DNA/protein damage), Nrf2-response readouts, and mitochondrial dysfunction indicators (e.g., membrane potential and respiratory impairment). However, these measures are often indirect and context-dependent in humans, and disc-specific sampling remains challenging.
2. Mitochondria and Cellular Respiration
Mitochondria are central regulators of aerobic energy production, generating adenosine triphosphate (ATP) through the electron transport chain (ETC) during oxidative phosphorylation, and forming the primary source of endogenous ROS [18]. During normal physiological respiration, approximately 1%–2% of molecular oxygen consumed is converted into the superoxide anion. Superoxide production mainly occurs at complexes I and III of the ETC. Superoxides are quickly converted to H2O2 by the superoxide dismutases (SOD) (Fig. 3). H2O2 generated in the mitochondrial intermembrane space by SOD1 can then diffuse into the cytosol, participating in broader cellular signaling pathways [19]. Surprisingly, mitochondria are simultaneously both major generators of ROS and primary targets for their damaging effects, with mitochondrial ROS production often perturbed in metabolic and inflammatory diseases. Oxidative damage compromises mitochondrial DNA (mtDNA) and lipids, further exacerbating ETC dysfunction [20]. To limit redox drift and preserve mitochondrial function, cells employ mitochondrial quality control programs that operate across proteostasis, antioxidant defense, mitochondrial dynamics, biogenesis, and selective organelle disposal. At the proteostasis level, the mitochondrial unfolded protein response induces mitochondrial chaperones (e.g., heat shock protein 60 and 70) and proteases to refold or remove damaged proteins, while mitochondrial antioxidant systems constrain ROS within a physiological range. When damage accumulates, mitochondrial dynamics segregate dysfunctional regions through dynamin-related protein-1-dependent fission, balanced by mitofusin and optic atrophy 1-mediated fusion, and functional capacity is replenished by biogenesis programs coordinated by peroxisome proliferator-activated receptor gamma coactivator-1α as well as mitochondrial transcription factor A. Irreversibly damaged mitochondria are eliminated by mitophagy, most classically via the PTEN-induced kinase 1/Parkin pathway or receptor-mediated routes (e.g., BNIP3/NIX and FUNDC1). In this way, mitochondrial quality control maintains a healthy mitochondrial pool, restrains excessive ROS production, and supports disc cell viability under OS [21,22].
3. Cellular Antioxidant Defense Mechanisms
Cells have evolved a sophisticated antioxidant system to maintain redox homeostasis and counteract the damaging effects of ROS [15,23,24]. Enzymatic antioxidants form the first line of defense, including SOD, catalase (CAT), glutathione peroxidases (GPx), and the thioredoxin (Trx) system (Fig. 3). The aforementioned SODs catalyze the dismutation of O2·− into H2O2. Mammals possess 3 major SOD isoforms: cytosolic Cu/ZnSOD (SOD1), mitochondrial MnSOD (SOD2), and extracellular SOD (SOD3) [25]. SOD2 is particularly critical for neutralizing mitochondrial ROS in NP cells [4]. CAT is able to decompose H2O2 into water and oxygen, preventing the formation of the highly toxic hydroxyl radicals via the Fenton reaction. GPX help reduce H2O2 and lipid hydroperoxides using glutathione (GSH) as a cofactor. Notably, GPX4 is a unique selenoprotein essential for repairing peroxidized lipids in membranes, thereby acting as the key suppressor of ferroptosis in IVD cells [26]. The Trx system, consisting of NADPH, Trx, and Trx reductase, regulates protein sulfhydryl groups and maintains cellular redox balance [27]. A second line of defense are the nonenzymatic antioxidants consisting of low molecular weight scavengers, with GSH being the most abundant intracellular thiol that maintains redox balance. Additional key antioxidants include vitamins C and E, carotenoids, and melatonin [28].
Lastly, the Nrf2 pathway serves as the master regulator of the cellular adaptive antioxidant response. Its regulation is tightly controlled by the cytosolic inhibitor Kelch-like ECH-associated protein 1 (Keap1). Under basal conditions, Keap1 targets Nrf2 for ubiquitination and proteasomal degradation. Keap1 possesses highly reactive cysteine residues that act as redox sensors. Upon exposure to electrophiles or ROS, these cysteines are modified, inducing a conformational change in Keap1 that halts Nrf2 ubiquitination. Stabilized Nrf2 translocates to the nucleus, heterodimerizes with small Maf proteins, and binds to antioxidant response elements in the promoter regions of cytoprotective genes (Fig. 3) [29,30]. In the IVD, Nrf2 activation upregulates a battery of antioxidant enzymes, including heme oxygenase-1, NADPH quinone dehydrogenase 1, SOD, and CAT. Furthermore, Nrf2 actively represses the NF-κB signaling pathway, thereby dampening inflammation and inhibiting the expression of matrix-degrading enzymes [31]. In degenerative discs, Nrf2 expression initially increases as a compensatory mechanism but eventually declines in advanced stages of degeneration, suggesting an “exhaustion” of this adaptive response. Therapeutic activation of Nrf2 has been shown to protect NP cells from OS-induced apoptosis and senescence [32].
4. OS and Inflammation
Chronic inflammation and OS are closely linked, sharing regulatory pathways and feedback loops. ROS act as central regulators of inflammatory signaling [18]. A major redox-sensitive target is the NF-κB pathway, where ROS can enhance IκB kinase activity, promoting the phosphorylation, ubiquitination, and proteasomal degradation of inhibitor of κBα. This releases NF-κB, enabling its nuclear translocation and the transcription of proinflammatory cytokines (e.g., interleukin [IL]-1β, tumor necrosis factor [TNF]-α, and IL-6) as well as catabolic enzymes (Fig. 3) [15,33,34]. ROS also activate the mitogen-activated protein kinase (MAPK) cascade, by oxidizing and inhibiting Trx, leading to its dissociation from apoptosis signal-regulating kinase 1 (ASK-1). Freed ASK-1 activates the c-Jun N-terminal kinase (JNK) and p38/MAPK pathways, which are critical transducers of mechanical and osmotic stress in the disc, promoting apoptosis and senescence [15,24,33]. In addition, mitochondrial ROS can enhance JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling, particularly STAT3 activation. Phosphorylated STAT3 can translocate to mitochondria and interact with gene related to interferon-β- and retinoic acid-induced mortality-19, further amplifying ROS production and facilitating necroptosis [24,35].
The convergence of these pathways results in the secretion of proinflammatory cytokines that further induce ROS generation in neighboring cells. Mitochondrial ROS are potent triggers for the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which facilitates the maturation and secretion of IL-1β. This process creates a self-sustaining cycle where inflammation fuels OS, and OS fuels inflammation. OS and chronic inflammation accelerate cellular senescence. Senescent cells secrete the senescence-associated secretory phenotype (SASP), a mixture of inflammatory factors and ECM-degrading proteases that reinforce local inflammation. Furthermore, the resulting tissue damage releases damage-associated molecular patterns (DAMPs), which bind to pattern recognition receptors (e.g., Toll-like receptor-4) and intensify the inflammatory response, accelerating ECM degradation [18,36].
Since vascularization is confined to the CEPs and outer AF [37], regions such as the NP and inner annulus experience markedly limited nutrient and gas supply [1]. This creates a unique and chemically constrained niche. Although local values vary by disc level, distance from the endplates, and overall disc health, typical estimates indicate about 2% O2 tension, roughly 1 mmol/L glucose, an osmolarity of about 430–496 mOsm/L (driven largely by the anionic proteoglycan-rich ECM that attracts and localizes cations), lactate concentrations near 5 mmol/L, and a pH around 7.0–7.2, which is about 0.5 units lower than surrounding tissues [2]. These values become even more strenuous with progression of IDD, inflammation, aging, etc [1]. As such, this environment requires endemic NP and AF cells to rely on specialized metabolic and structural strategies to maintain viability.
1. Hypoxia and HIF-Driven Adaptation
First, due to limited oxygen availability, the cells need to adjust ATP production to favor glycolysis, despite limited glucose availability. Here, NP cells have been reported to have constitutively active HIF-1 and HIF-2 molecules (even under normoxic conditions), which function as transcription factors able to promote target genes activated by hypoxia-response elements [38]. HIF-2 normally regulates antioxidant genes such as SOD2 [4]. This antioxidant program is dampened in NP cells, where hypoxia induces little measurable upregulation of its targets [38,39]. Alternatively, HIF-1 protects NP cells from oxidative damage by maintaining expression of the mitochondrial protein NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2), which under OS dampens complex I activity, thus reducing ROS production and restraining excessive mitophagy that may trigger apoptosis [40]. This metabolic adjustment limits reliance on oxidative phosphorylation, thereby controlling mitochondrial ROS production.
2. Glucose Limitation and Metabolic Rewiring
In addition, HIF-regulated pathways enhance anaerobic glycolysis by upregulating glucose transporters (e.g., GLUT-1, GLUT-3) and glycolysis-related enzymes (e.g., glyceraldehyde 3-phosphate dehydrogenase, pyruvate dehydrogenase kinase) while suppressing mitochondrial oxidative phosphorylation to reduce oxygen consumption [38]. Glycolysis yields only about 2 ATP per mole glucose compared with roughly 30 generated through mitochondrial metabolism, but does have a higher ATP turnover rate [38]. Within these constraints, the dominance of anaerobic glycolysis ensures that available carbon is used efficiently for ATP generation and ECM-supportive biosynthesis, while minimizing the burden on mitochondria and preserving redox balance [41,42]. This glycolytic bias also drives continual lactate production and accumulation, that contributes to the chronically acidic microenvironment of the IVD [43]. Moreover, glucose-deprived NP cells activate early-stage autophagy, providing short-term protection to NP cells by buffering stress and preventing apoptosis under nutrient restriction. However, prolonged glucose deprivation drives sustained endoplasmic reticulum stress, which shifts Activating Transcription Factor 4 (ATF4) signaling from early protective autophagy to excessive ROS generation, leading to OS and apoptosis [44]. Intriguingly, NP cells contain relatively few mitochondria and rely heavily on glycolysis for energy [45]. Moreover, HIF-1 drives mitochondrial fission and mitophagy initiation in NP cells by activating the Bcl-2 interacting protein 3 (BNIP3)-dependent quality control pathway [46]. Together, these processes constitute a specialized mitochondrial quality control program in NP cells, driven primarily by HIF-1/BNIP3 mitophagy, hypoxia-induced mitochondrial fragmentation, and NDUFA4L2. By removing damaged mitochondria, maintaining membrane potential, and limiting ROS, these adaptations leave IVD cells energetically restricted and vulnerable to shifts in nutrient or metabolic balance.
3. Hyperosmolarity and Osmoregulatory Control
To cope with the high osmolarity, NP cells employ a range of ion-transport channels to maintain volume, intracellular ionic balance, and protein function. Strong expression is seen in AQP water channels and the osmotic-sensing channel transient receptor potential vanilloid 4 (TRPV4), which facilitate water flux and calcium-mediated volume regulation under hyperosmotic stress [47]. These channels enable disc cells to detect osmotic shifts and rapidly adjust water and ion movements. Tonicity-responsive enhancer binding protein (TonEBP) serves as the central osmoprotective transcription factor, sensing hyperosmotic load and inducing key osmolyte transporters such as myo-inositol transporter, betaine/GABA transporter 1, and taurine transporter, which accumulate compatible osmolytes to stabilize macromolecular function without disturbing biochemical reactions [48]. TRPV4 also integrates osmotic and mechanical cues, influencing inflammatory signaling and cytoskeletal organization, thereby helping NP cells maintain structural integrity under fluctuating load conditions [49]. When TonEBP or these volume-regulating channels are disrupted, impaired osmoadaptation can disturb survival pathways such as phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), increasing mitochondrial vulnerability, which drives ROS accumulation in NP cells [50]. Because osmotic adjustments depend on continuous ion pumping and osmolyte cycling, these processes impose notable energetic demands [51]. Thus, reduced ATP availability can impair ion pump efficiency, contributing to ionic imbalance and increased cellular stress. As IDD progresses and proteoglycan content declines, disc osmolarity falls, altering TonEBP mediated osmolyte regulation. This shift may diminish the osmoprotective capacity of NP cells and potentially increase their susceptibility to oxidative challenges, but this requires further investigation.
4. Acidic Stress and pH Homeostasis
Finally, to counter the sustained acidity generated by lactate accumulation [43], disc cells fine-tune pH regulation through coordinated proton handling. They rely on proton extrusion via Na+/H+ exchangers, bicarbonate transporters, while also using intracellular buffers that stabilize pH despite an extracellular environment of pH 7.0, or lower in IDD cases [52,53]. These mechanisms prevent acidification that would impair enzyme activity, matrix synthesis, and cytoskeletal stability [54]. Similar to ion-transport channels, proton exchangers require ATP, meaning that excessive acidity increases metabolic strain. In addition, low pH destabilizes mitochondrial membrane potential, elevating both mitochondrial and cytosolic ROS, and acidic conditions heighten cellular sensitivity to catabolic signaling from inflammatory cytokines [55]. Together, these effects underscore the importance for NP and AF cells to tightly regulate pH and associated chemical cues to maintain redox balance and cellular homeostasis.
These pathways capture only part of the broader adaptive landscape of IVD cells, and many regulatory mechanisms remain under active investigation. Even so, they collectively stabilize redox balance, support matrix production, and maintain homeostasis within the extreme physicochemical constraints of the avascular disc. Yet the same adaptations that protect NP and AF cells under stable conditions can heighten vulnerability when nutrient supply, mechanical load, or mitochondrial function is disrupted, since even minor deviations are speculated to overwhelm their metabolic and redox reserves.
IDD is driven by cellular dysfunction, with OS acting as a primary mechanism rather than a mere byproduct [56]. ROS regulate matrix metabolism, cell death, senescence, and inflammation, and ROS levels in NP cells correlate positively with degeneration severity [4,57]. Excessive ROS directly damage macromolecules, impair cellular function, and accelerate structural failure.
1. OS-Induced Senescence and Cell Death
Sustained OS profoundly impacts the fate of disc cells, depleting the functional cell pool through the induction of senescence and cell death [58]. Cellular senescence, an irreversible cell cycle arrest arising from unresolved cellular damage [59], is a hallmark of IDD, and its accumulation contributes directly to disease progression. OS is a major driver of stress-induced premature senescence (SIPS), primarily through activation of the p53-p21-Rb and p16INK4a-Rb pathways. Particularly, H2O2-mediated ROS-signaling promotes G0/G1 arrest via these mechanisms [58,60], with p16 functioning as both a marker and mediator of this response [61]. Genetic strategies to reduce p16 expression have been shown to delay IDD and reduce OS levels, suggesting that targeting this pathway holds therapeutic promise. Agents such as rapamycin, which target cellular metabolic pathways, have been shown to suppress ROS generation and p16-positive cell proliferation, thereby offering protection against SIPS [58,62].
Alternatively, excessive OS-induced mitochondrial damage and dysfunction decreases mitochondrial membrane potential and enable the leakage of pro-apoptotic factors, such as cytochrome c [22,63]. Pathological stressors, such as chronic mechanical compression and the accumulation of advanced glycation endproducts (AGE), are known to activate this specific apoptotic cascade [64]. The application of mitochondria-targeted antioxidants can successfully abrogate these mitochondrial ROS surges and restore cell viability [63]. Beyond classical apoptosis, OS also drives additional forms of regulated cell death that contribute to disc pathology. One of these is ferroptosis, an iron-dependent process marked by lethal lipid peroxidation. Oxidant exposure induces ferroptosis in both AF and NP cells, accompanied by reduced levels of protective enzymes such as GPX4 and the iron storage protein Ferritin heavy chain, together with increased expression of lipid peroxidation-promoting factors including Acyl-CoA synthetase long-chain family member-4 (ACSL4) and Prostaglandin-Endoperoxide Synthase-2 (PTGS2) [26]. This pathway is tightly connected to antioxidant defenses, as suppression of Sirtuin-3 intensifies OS-induced ferroptosis in NP cells [65]. OS further amplifies this cascade by promoting ferritinophagy through the nuclear receptor coactivator-4 receptor, releasing free iron and escalating lipid peroxidation [26]. Alternatively, pyroptosis is characterized by its strong inflammatory profile. Mitochondrial dysfunction under severe OS conditions can open the mitochondrial permeability transition pore, causing mitochondrial DNA to leak into the cytosol. The released mtDNA functions as a DAMP sensed by the “cyclic GMP-AMP synthase-stimulator of interferon genes” (cGAS-STING) pathway, which subsequently activates the NLRP3 inflammasome [66]. This leads to the maturation and secretion of inflammatory cytokines and results in inflammatory cell death.
2. Autophagy
Autophagy is a cellular quality control pathway that clears damaged proteins and organelles, recycling substrates to maintain energy and redox homeostasis. In the avascular IVD, autophagy is particularly relevant because chronic hypoxia and nutrient limitation can promote reactive ROS accumulation and proteotoxic stress. Yurube et al. [62,67] have highlighted that coordinated autophagy and mTOR signaling helps disc cells adapt to these constraints; however, dysregulation may contribute to age- and degeneration-related loss of homeostasis. Available models suggest a context- and stage-dependent role. In AF cells, nutrient deprivation increases autophagic flux, consistent with an adaptive survival response [68]. In a rat tail static compression model, NP tissue shows more prominent basal autophagy than AF, but sustained compression reduces autophagy in both compartments, implying that prolonged mechanical stress can exhaust this protective program and facilitate degeneration [69]. Collectively, these findings support autophagy as a buffering mechanism near the redox threshold; when impaired, dysfunctional mitochondria may accumulate, amplifying ROS burden and susceptibility to senescence and regulated cell death. Therapeutically, autophagy modulation is a plausible redox-adjacent strategy, but timing and target engagement are critical. Yurube et al. [70] reported that rapamycin mitigates inflammation-associated matrix dysregulation by inhibiting mechanistic target of rapamycin complex 1 and inducing autophagy through PI3K/Akt/mTOR signaling, supporting mTOR–autophagy control as a candidate target in IVD degeneration. Future studies should incorporate biomarkers of autophagic flux together with redox and senescence readouts to define stage-appropriate windows for intervention and to avoid disrupting physiological stress adaptation.
3. Inflammatory Response
The pathogenesis of IDD is sustained by a self-perpetuating vicious cycle between inflammation and OS [57]. Senescent cells secrete the SASP, which comprises a complex array of proinflammatory cytokines, chemokines, and matrix-degrading enzymes, such as matrix metalloproteinases (MMP) and a “disintegrin and metalloproteinase with thrombospondin motifs” (ADAMTS) [4,61,71]. This paracrine secretion maintains a catabolic and proinflammatory microenvironment that extends far beyond the senescent cell itself, promoting senescence and apoptosis in surrounding healthy IVD cells. Reducing the burden of senescent cells through targeted interventions has been shown to reduce the expression of key inflammatory factors, including TNF-α, IL-1β, and IL-6 [72-74].
OS is a primary upstream activator of major proinflammatory transcription factor pathways. the aforementioned NF-κB pathway and MAPK, promotes the massive transcription of proinflammatory cytokines and catabolic enzymes, such as inducible nitric oxide synthase, cyclooxygenase-2, and inflammatory cytokines [75,76]. IL-1β release is a hallmark of disc inflammation, often mediated by NLRP3 inflammasome activation. Mitochondrial ROS is essential for the activation and assembly of the NLRP3 inflammasome. Oxidative damage markers, such as AGEs, promote robust ROS generation, directly leading to NLRP3 activation and subsequent IL-1β secretion [71,77]. This inflammatory environment then amplifies OS, creating a positive feedback loop. TNF-α is known to induce further ROS generation in disc cells [78,79]. This positive feedback loop, where chronic inflammation generates more ROS, which in turn sustains inflammatory signaling, is a critical mechanism driving uncontrolled IDD progression.
4. Metabolic Shift and Matrix Remodeling: From Chondrogenesis to Fibrosis
OS severely compromises the integrity of the ECM by disrupting the balance between matrix synthesis and degradation, fundamentally altering the cell phenotype. Exposure to elevated oxygen tension or oxidants significantly upregulates the expression of key matrix-degrading enzymes, including MMP-1, MMP-3, MMP-13, ADAMTS4, and ADAMTS5 [57,80]. Concurrently, OS severely suppresses the expression of anabolic markers, such as aggrecan and type II collagen [4,81]. The relentless destruction of ECM components, coupled with the intrinsic lack of regenerative capacity of the IVD [82], leads the gelatinous, proteoglycan-rich NP tissue to gradually be replaced by a disorganized, fibrocartilaginous matrix, marked by the pathological substitution of type II collagen with type I collagen [60]. This transition reflects the cellular shift from a matrix anabolic phenotype to a matrix catabolic and proinflammatory state. Furthermore, the excessive ROS induces post-translational oxidative modification of matrix components [83], and elevated levels of AGEs are detected in aged and degenerative human discs [4,64]. These oxidative modifications cause collagen cross-linking, which increases ECM stiffness and reduces elasticity. These structural changes impair the disc’s biomechanical function, further exacerbating cell mechanical stress.
5. Clinical Translation: From Microenvironment to Symptoms
IDD is a major driver of chronic LBP, and increasing evidence links OS to both structural deterioration and symptom development. Higher OS levels correlate with more advanced anatomical degeneration, and genetic models with elevated ROS, such as Sod2-knockout mice, show markedly accelerated age-related and mechanical stress-related IDD and associated with enhanced pain phenotypes [4]. Furthermore, OS contributes critically to CEP degeneration [57,84]. OS-induced processes, including the promotion of inflammation and the inhibition of endogenous defense mechanisms such as Nrf2, promote degeneration, ferroptosis, and subsequent calcification in the CEP [32]. This pathological calcification acts as a hardened barrier, reducing the nutrient supply to the NP and thus intensifying the hostile microenvironment of the disc. Proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, play a key role in discogenic pain [85]. The OS-driven inflammatory state is essential for nociception. The persistent secretion of SASP factors and inflammatory mediators sensitizes nerve endings, contributing to chronic LBP [79,86]. Animal studies confirm that increased OS levels correlate with worse pain-related behavioral scores [65]. Moreover, as IDD is accompanied by vascular and nerve ingrowth, this process is exacerbated by OS. Evidence suggests that reducing senescent cell burden and lowering OS levels, such as through p16 deletion, can decrease the expression of angiogenic factors [73], highlighting OS as an upstream mechanism governing these structural changes. Additionally, ROS-mediated inflammation, particularly IL-1β signaling, promotes the production of neurotrophic factors, such as vascular endothelial growth factor, nerve growth factor, and brain-derived neurotrophic factor, which are strongly correlated with IDD severity and disc innervation [87].
Collectively, the literature supports a stage-dependent model in which OS can act both as an initiating stressor and as a self-reinforcing amplifier of IDD. In early degeneration, moderate ROS participate in redox signaling and may trigger compensatory programs, including antioxidant responses, to preserve cellular and ECM homeostasis. However, as degeneration progresses, compensatory capacity becomes exhausted, mitochondrial dysfunction becomes more prominent, and inflammation-ROS feed-forward loops emerge. In this setting, OS does not merely accompany IDD; it actively facilitates progression by depleting the functional cell population through apoptosis and senescence, degrading matrix integrity, and sustaining chronic inflammation, ultimately undermining the biomechanical and structural integrity of the IVD. Beyond structural degeneration, OS also contributes to painful clinical symptoms by promoting vascular and nerve ingrowth. Recognizing OS as a central pathogenic mechanism, particularly in the transition from adaptive redox control to redox breakdown, underscores the therapeutic promise of antioxidant and mitochondria-targeted strategies in IDD management.
The treatment of discogenic LBP is mainly based on symptom-relieving approaches, ranging from conservative strategies (e.g., analgesic drugs, physical therapy) to surgical interventions (e.g., fusion, total disc replacement). However, while often yielding satisfactory outcomes, these therapies do not directly target the degenerative process [9]. As outlined above, OS is a complex mechanism associated with local inflammation, cell death and senescence, matrix remodeling, metabolic disruption and tissue neoangiogenesis and neoinnervation [12]. Therefore, it is plausible to speculate that tackling OS would blunt its detrimental effects on the IVD microenvironment and resident cells, thus potentially attenuating degenerative cascades and slowing progression when applied at appropriate stages [17]. To date, several antioxidant strategies against IDD have been described in the literature (Table 1). However, these approaches have been mainly tested in preclinical settings, with limited direct human interventional data, and real-world efficacy remains to be confirmed [81]. Broad antioxidant strategies have produced mixed or modest benefits in several chronic degenerative diseases, often due to limited target engagement, inappropriate timing, and the risk of suppressing physiological redox signaling. Disc biology adds additional constraints, including avascular diffusion-limited exposure and compartment-specific redox vulnerability, suggesting that successful translation will likely require stage-matched intervention windows, biomarker-confirmed target engagement, and delivery approaches that achieve durable intradiscal exposure rather than nonspecific systemic scavenging.
1. Pharmacological Antioxidants
Antioxidant molecules for IDD fall in 4 main categories i.e., ROS scavengers, drugs, hormones, and natural products [81].
Among ROS scavengers, GSH and its precursor N-acetyl cysteine have shown to reduce ROS levels, cell apoptosis, and ECM catabolism, and CEP calcification for both human and rat cells [78,84,88,89]. As a cofactor of mitochondrial dehydrogenase, pyrroloquinoline has been demonstrated to decrease H2O2-induced ROS production and ECM catabolism, as well as to downregulate Bcl2-mediated caspase-dependent mitochondrial apoptosis in NP cells [56]. Mitoquinone is a mitochondria-specific antioxidant able to inhibit lipid peroxidation thus maintaining transmembrane potential, limiting ROS production, and consequent compression-induced apoptosis in human NPC cells [63]. Fullerols, polyhydroxyl derivatives of fullerenes, are able to bind and chemically inactivate free radicals, demonstrating to reduce collagen type II catabolism in an animal model [90].
Among commonly used pharmacological agents, metformin has been shown to attenuate NP cell senescence by suppressing the OS-induced cGAS-STING pathway via autophagy, as well as to reduce NP cell apoptosis through downregulation of the p53/p21/Rb and p16/Rb signaling axes [72,91]. Notably, a recent large-scale prospective study reported that metformin use was associated with a significantly reduced risk of developing IDD over a follow-up period of up to 13 years [92]. Vitamin D, widely prescribed as a supplement for osteoporosis, has also emerged as a relevant modulator of IDD. Vitamin D receptor (VDR) expression declines with increasing IDD, and vitamin D has been shown to counteract OS, cellular senescence, apoptosis, and ECM degradation in IVD cells exposed to H2O2 and IL-1β, both in vitro and in vivo. These protective effects appear to be mediated through activation of the PI3K/Akt pathway and inhibition of NF-κB signaling [93,94]. VDR-overexpression has been demonstrated to promote mitophagy and prevent apoptosis and mitochondrial injury under OS [95]. Additionally, other drugs, including aspirin, isopentobarbital, amobarbital, ulinastatin, laquinimod, and quinazoline, have demonstrated promising antioxidant properties both in vitro and in vivo [57,81].
Melatonin is a hormone physiologically secreted by the pineal gland, primarily involved in circadian rhythm regulation, but also characterized by antioxidant and anti-inflammatory properties. Melatonin has been shown to reduce ROS production and OS-induced apoptosis while promoting autophagy in NP and CEP cells. In parallel, melatonin enhances ECM homeostasis by upregulating aggrecan, SRY-box transcription factor 9, and type II collagen expression, while suppressing the catabolic enzymes MMP-13 and ADAMTS-5. These protective effects are mediated predominantly through activation and inhibition of PI3K/Akt and NF-κB signaling pathways, respectively [96]. Estrogens, the primary female sex hormones, play a crucial role in maintaining IVD homeostasis. Under physiological conditions, estrogen attenuates IL-1β–induced apoptosis of NP cells and limits ECM catabolism [97]. Moreover, antioxidant defenses, SOD, GSH, and total serum antioxidant capacity, are significantly higher in healthy animals compared with estrogen-deficient ovariectomized rats. Consistently, reduced estrogen levels have been associated with more severe IDD [81]. Likewise, parathyroid hormone has been shown to increase the expression of SOD1, SOD2, dampen tissue inflammation, NP cell apoptosis, and stimulate ECM synthesis through the Sonic hedgehog pathway [98].
Recently, many natural phytochemicals have gathered attention for their antioxidant effects, although their efficacy is based mainly on in vitro and some in vivo evidence. Investigated compounds include curcumin, resveratrol, mangiferin, icariin, lycopene, sesamin, salvialonic acid, naringin, berberine, quercetin, and several more. A deeper description of the mechanisms involved goes beyond the scopes of this study and is extensively reviewed elsewhere [5].
2. Lifestyle Interventions
In a nationwide cross-sectional survey of Japanese adults, LBP was associated with several lifestyle-related factors, including higher body mass index, alcohol consumption, dyslipidemia, and smoking; pain severity was additionally associated with lack of exercise [99]. Intradiscal OS is markedly aggravated by several conditions and lifestyle factors, including diabetes, obesity, and smoking. Elevated glucose levels and AGE accumulation promote OS by activating the NLRP3 inflammasome [77] and accelerating disc cell senescence [100]. Similarly, cigarette smoking not only introduces exogenous ROS but also enhances OS through ER stress and mitochondrial dysfunction [6]. Excess body weight and obesity, often accompanied by the low-grade systemic inflammation characteristic of metabolic syndrome, further amplify OS and contribute to IDD progression [14]. Collectively, these observations suggest that maintaining a healthy body weight, quitting smoking, and achieving good glycemic control may help mitigate OS and slow related degenerative processes. Interestingly, a recent in vivo study employing a rat model of IDD has shown that massage therapy reduced mechanical allodynia, thermal hyperalgesia, and ROS levels, while increasing GSH and SOD expression. However, these results remain largely preliminary and need to be confirmed under more strict experimental conditions [101].
3. Novel Biotechnologies
Over the past decade, several innovative therapeutic strategies involving the intradiscal delivery of biomaterials, cells, and extracellular vesicles (EVs) have demonstrated promising antioxidant effects. Hydrogels have attracted considerable interest due to their NP-mimicking properties and their ability to function as local drug delivery systems, enabling sustained release of antioxidant compounds [102,103]. Intradiscal administration of mesenchymal stromal cell has also been shown to exert pronounced anticatabolic and antioxidant effects both in vitro and in vivo, largely attributable to their capacity to differentiate toward an NP-like phenotype and to secrete growth factors and anti-inflammatory cytokines [82]. Among these paracrine mediators, EVs have emerged as particularly attractive candidates because of their ability to transport a broad range of bioactive molecules with regenerative potential [104]. EVs derived from multiple cell sources, including Wharton’s jelly, bone marrow, and platelets, have been reported to attenuate OS by preserving mitochondrial function, reducing ROS production, and modulating the expression of OS-related markers such as SOD1, SOD2, and Nrf2.105,106 Notably, these approaches are not mutually exclusive and may be combined into integrated therapeutic platforms, offering complementary structural, biochemical, and biological cues to mitigate OS and potentially promote IVD repair.
4. Who to Treat and When: Patient Cohorts and Disease Stages
Redox-targeted therapies are most likely to be effective when matched to disease stage and dominant biology. Stage mismatch may be a key reason for inconsistent translation. In early-to-mid-stage IDD, viable disc cells and residual matrix remain, making antioxidant or mitochondrial quality control interventions more plausible as disease-modifying strategies. In advanced-stage IDD with severe collapse, fibrosis, endplate damage, and low cellularity, redox modulation alone is unlikely to reverse structure; strategies such as senolytic and anti-inflammatory interventions may be required before regenerative attempts, with goals shifting toward symptom control and slowing progression. Cohorts most suitable for redox-targeted strategies include patients with higher systemic oxidative burden or active inflammatory-redox coupling, such as those with diabetes, obesity, or smoking history, and patients with early-to-mid-stage degeneration in whom disc architecture is still preserved. To translate this stage-aware logic into clinical trial design, enrollment and endpoints should be aligned to biological feasibility. Practical stratification can combine (1) structural stage (e.g., disc height preservation and degeneration grade), (2) a minimal redox-senescence phenotype (e.g., oxidative damage markers and senescence/SASP signatures), and (3) transport failure indicators (e.g., endplate deterioration or permeability proxies on imaging). For early-to-mid- stage disease with preserved architecture, realistic primary outcomes include pain, function, and evidence of target engagement (e.g., redox and senescence biomarker shifts) and quantitative imaging measures. For advanced-stage disease, structural reversal is unlikely; therefore, primary outcomes should prioritize pain, function, and safety, while biomarkers are best positioned as mechanistic secondary endpoints. This approach provides testable, stage-matched predictions for enrichment, dosing window selection, and endpoint choice.
5. How to Deliver
A major translational bottleneck for OS-modulating therapies is the disc’s transport barrier and the resulting heterogeneity of intradiscal exposure in an avascular, diffusion-limited tissue. Because the IVD is avascular and relies largely on diffusion across the CEP, intradiscal exposure after systemic dosing can be limited and uneven, particularly as endplate permeability declines during degeneration. The dense, highly charged ECM further restricts penetration and retention of many compounds, and the harsh microenvironment can reduce cellular responsiveness and shorten effective drug action. Accordingly, delivery strategies should maximize local residence time (e.g., sustained-release depots), improve intradiscal distribution (e.g., matrix-interactive or stimulus-responsive carriers), and minimize iatrogenic injury through appropriate dosing, needle size, and injection protocols. Each delivery strategy has distinct trade-offs and different levels of near-term feasibility. Systemic approaches are scalable and may address whole-body drivers of OS, but they can cause off-target effects and may not achieve sufficient intradiscal exposure. Local or intradiscal delivery can maximize local bioavailability and reduce systemic exposure, but remains largely investigational for most redox-modulating payloads, with procedural risks (e.g., infection, bleeding, nerve irritation, and needle injury) and strict constraints on dosing, retention, and biomaterial compatibility. Mitochondria-targeted antioxidants offer mechanistic specificity for mitochondrial ROS and quality control pathways, but require rigorous evaluation of biodistribution and safety. Sustained-release depots, matrix-interactive carriers, and cell or EV platforms are promising but remain experimental or early phase, with the need for clearer standards for distribution, batch consistency, and long-term safety. More broadly, clinical translation has lagged despite robust preclinical efficacy, likely reflecting the convergence of limited and heterogeneous intradiscal exposure, disease-stage heterogeneity, imperfect alignment between acute injury models and chronic human degeneration, and endpoints that do not capture redox- or senescence-specific target engagement. These constraints reinforce the need for biomarker-enriched, stage-matched trials and delivery approaches that ensure durable, compartment-appropriate intradiscal exposure.
Despite growing evidence implicating OS as a central driver of IDD, its translation into clinically effective interventions remains limited. Future research should adopt a structured, biomarker-driven roadmap to enable precision medicine approaches. First, priority should be given to the identification and validation of biomarkers of intradiscal OS, putatively including indicators of oxidative damage, antioxidant defense pathways (e.g., SOD2, GPX [4,26]), ferroptosis-related markers (e.g., ACSL4 [25]), and mitochondrial dysfunction indicators. These molecular signatures should be integrated with advanced quantitative imaging biomarkers, which could possibly serve as a noninvasive proxy of redox imbalance and disc health [107,108]. In this regard, prospective clinical cohorts of discogenic LBP patients with longitudinal biospecimen and imaging collection will be essential to establish prognostic and predictive validity. Second, combining molecular, imaging, and clinical data will allow patient stratification into biologically meaningful endotypes (e.g., ferroptosis-dominant, senescence-dominant, or inflammation-driven IDD) [109]. Such stratification is critical to move beyond “one-size-fits-all” interventions and to identify patients most likely to benefit from targeted redox-modulating therapies. Third, future therapeutic strategies should focus on combination approaches that address multiple pathogenic mechanisms simultaneously [9]. Promising avenues include pairing mitochondria-targeted antioxidants or Nrf2 activators with anti-inflammatory agents, senolytics [74], or regenerative biotechnologies [82]. Local intradiscal delivery systems may enhance efficacy while minimizing systemic toxicity. Finally, biomarker-enriched and adaptive clinical trial designs are needed to demonstrate biological efficacy and clinically relevant disease modification. Establishing standardized protocols, biobanks, and multicenter consortia will be essential to accelerate translation from experimental redox biology to personalized therapies for IDD.
OS is a key driver of IDD, combining mitochondrial dysfunction, inflammation, cell senescence and death, ECM breakdown, and pain-relevant structural changes. Therapeutic approaches that restore redox balance (e.g., mitochondria-targeted antioxidants, drugs and hormones with antioxidant effects, lifestyle measures, and emerging biological approaches) are promising but remain largely preclinical. Future research should determine whether effective modulation of OS can translate into durable, clinically meaningful improvements in IVD structure, biochemistry, and patient-reported outcomes.

Conflict of Interest

The authors have nothing to disclose.

Funding/Support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contribution

Conceptualization: ST, JS, LA, DS; Methodology: ST; Project administration: ST; Visualization: ST, JS; Writing – original draft: ST, JS, LA; Writing – review & editing: ST, JS, LA, HN, MI, DS.

Fig. 1.
Adapt-Mitigate-Target framework of oxidative stress in intervertebral disc degeneration. Disc cells adapt to an extreme microenvironment through metabolic rewiring and redox homeostasis to maintain extracellular matrix integrity. Failure of these mechanisms leads to redox imbalance, mitochondrial dysfunction, inflammation, cellular senescence, and matrix degeneration. Therapeutic strategies aim to restore redox balance and target downstream degenerative pathways to potentially stabilize disc structure and function. AF, annulus fibrosus; ECM, extracellular matrix; NP, nucleus pulposus; ROS, reactive oxygen species; HIF-1/2, hypoxia-inducible factor 1/2; EV, extracellular vesicle.
ns-26420332-0166f1.jpg
Fig. 2.
Schematic overview of redox homeostasis and redox imbalance in intervertebral disc degeneration. (A) Under physiological conditions, a balance is maintained between oxidant production and antioxidant defenses. Degenerative factors increase reactive oxygen species while antioxidant capacity declines, leading to redox imbalance and oxidative stress. This imbalance may be mitigated or restored through targeted biological and regenerative therapies. (B) The intervertebral disc relies on functional NP, AF, and CEP cells to maintain extracellular matrix homeostasis. Once a redox threshold is exceeded, oxidants and ROS, which are normally part of physiological signaling, trigger a cascade of cellular dysfunction, matrix degradation, and tissue damage that self-propagates and progressively deteriorates disc structure. AF, Annulus fibrosus; CEP, Cartilage endplates, ECM, Extracellular matrix; NP, Nucleus pulposus; ROS, reactive oxygen species.
ns-26420332-0166f2.jpg
Fig. 3.
Simplified schematic of cellular redox balance and redox signaling in intervertebral disc cells. Reactive oxygen species (ROS) arise from mitochondrial electron transport chain activity and membrane associated NADPH oxidase (NOX2). Superoxide (O2·−) is converted to hydrogen peroxide (H2O2) by superoxide dismutases (SOD1, SOD2, SOD3), with H2O2 acting as both a signaling molecule and a source of oxidative stress after diffusion through aquaporins (AQPs). Antioxidant systems including catalase, glutathione peroxidases, peroxiredoxins, and the thioredoxin system detoxify ROS and preserve redox homeostasis. Excess ROS activate stress pathways such as ASK1 mediated JNK and p38 signaling, while redox-sensitive transcriptional programs including NRF2 and NF-κB coordinate cytoprotective or catabolic responses. The balance between these pathways determines cellular fate. ROS, reactive oxygen species; NOX2, NADPH oxidase 2; SOD, superoxide dismutase; GPx, glutathione peroxidase; PRx, peroxiredoxin; TRx, thioredoxin; TRxR, thioredoxin reductase; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2 related factor 2; NFκB, nuclear factor kappa B; IκB, inhibitor of nuclear factor kappa B; ASK1, apoptosis signal-regulating kinase 1; JNK, c-Jun N-terminal kinase; p38, p38 mitogen-activated protein kinase; GSH, reduced glutathione; GSSG, oxidized glutathione; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; NADP+, nicotinamide adenine dinucleotide phosphate, oxidized form; ATP, adenosine triphosphate; ETC, electron transport chain.
ns-26420332-0166f3.jpg
Table 1.
Examples of therapeutic strategies targeting oxidative stress in intervertebral disc degeneration
Table 1.
Intervention Proposed mechanism of action Experimental models (exposure) Route of administration Key outcomes Translation status References
ROS scavengers
 GSH ROS scavenging Human NP and CEP cells (H2O2, IL-1̠) In vitro Reduced ROS levels, apoptosis, ECM catabolism, and CEP calcification Preclinical [84, 88]
 N-acetyl cysteine ROS scavenging Human NP and rat AF cells (H2O2, BSO, TNF-α, DMSO) Oral Reduced ROS levels, ECM catabolism, and inflammation Preclinical [78, 89]
Rat IVD puncture model (in vivo)
 Pyrroloquinoline quinone Mitochondrial dehydrogenase cofactor Rat NP cells (H2O2) In vitro Reduced ROS levels, ECM catabolism, and mitochondrial apoptosis Preclinical [56]
 Mitoquinone Mitochondria-specific antioxidant Human NP cells (Compression) In vitro Inhibited lipid peroxidation, maintained membrane potential, limited ROS and apoptosis Preclinical [63]
 Fullerols ROS scavenging Human NP cells (H2O2, IL-1β) Intradiscal Reduced ROS levels and inhibition of ECM degradation Preclinical [90]
Rabbit IVD puncture model (in vivo)
Pharmaceutical drugs
 Metformin cGAS-STING pathway Human and rat NP cells (TBHP) Intraperitoneal (rat) Attenuated senescence and apoptosis via p53/p21/Rb and p16/Rb axes Clinical (observational) [72, 91, 92]
Autophagy Rat IVD puncture model (in vivo) Oral (human)
p53/p21/Rb axes Human cohort (observational) Reduced IDD risk in diabetic patients
 Vitamin D PI3K/Akt activation Rat and mouse NP cells (H2O2, IL-1β) Intraperitoneal (mouse and rat) Counteracted OS, senescence, apoptosis, and ECM degradation; and promoted mitophagy Preclinical [93, 94, 95]
NF-κB inhibition Mouse tail suspension model and rat IVD puncture model (in vivo)
 NMN NAD+ precursor Human NP cells (PQ) Intraperitoneal Attenuated ROS and cellular senescence; reduced mechanical stress-induced IDD and pain Preclinical [4]
SOD2 activation Mouse tail-looping model (in vivo)
Hormones
 Melatonin PI3K/Akt activation Human and mouse NP cells, rat Intradiscal (rabbit and rat) Reduced ROS, apoptosis; enhanced autophagy and ECM homeostasis Preclinical [96]
NF-κB inhibition NP/AF/CEP cells (H2O2, IL-1β, TNF-α, TBHP, high glucose, LPS compression) Intraperitoneal (rat)
Rabbit IVD puncture model (in vivo)
Rat IVD puncture model and tail compression model (in vivo)
 Estrogen Antioxidant capacity Rat NP cells (IL-1β) Not specified Attenuated IL-1β–induced apoptosis and limited ECM catabolism Preclinical [81, 97]
Rat ovariectomized model (in vivo)
 Parathyroid hormone Sonic hedgehog pathway Human NP cells (IL-1β) Subcutaneous Increased SOD1/SOD2 expression, dampened inflammation and apoptosis, stimulated ECM synthesis Preclinical [98]
Mouse tail suspension model (in vivo)
Lifestyle interventions
 Weight and glucose control Systemic OS and NLRP3 inflammasome Human NP cells, rat AF cells (AGEs, high glucose) In vitro AGEs/high glucose promote OS and senescence; obesity amplifies OS and IDD Clinical (observational) [14, 77, 100]
Human (observational)
 Smoking cessation Exogenous ROS and ER stress Mouse EP cells (iron) Inhalational Cigarette smoking enhances OS through ER stress and mitochondrial dysfunction Clinical (observational) [6]
Mouse iron overload model (in vivo)
Mouse and rat cigarette smoke exposure model (in vivo)
Human (observational)
 Massage therapy Mechanical stimulation Rat IVD puncture with intradiscal TNF-α injection model (in vivo) Massage therapy Reduced mechanical allodynia and ROS levels; increased GSH and SOD expression Preclinical [101]
Biotechnologies
 Hydrogels Drug delivery system In vitro and in vivo Intradiscal implantation Enabled sustained release of antioxidant compounds mimicking NP properties Clinical (early phase) [102, 103]
Human (IVD herniation)
 Mesenchymal stromal cells Paracrine signaling In vitro and in vivo Intradiscal Exerted anti-catabolic and antioxidant effects; differentiation toward NP-like phenotype Clinical (early phase) [82]
Reconstituting NP homeostasis Human (discogenic pain)
 Extracellular vesicles Transportation of a broad range of bioactive molecules Human and rat NP cells (H2O2, IL-1β) Intradiscal Attenuated OS by reducing ROS and modulating SOD1, SOD2, and Nrf2 Preclinical [104, 105, 106]
Rat IVD puncture model (in vivo)

ROS, reactive oxygen species; GSH, glutathione; NP, Nucleus pulposus; H2O2, hydrogen peroxide; IL-1β, interleukin-1β; CEP, cartilage endplate; ECM, extracellular matrix; AF, annulus fibrosus; BSO, buthionine sulfoximine; TNF-α, tumor necrosis factor-α; DMSO, dimethyl sulfoxide; cGAS-STING, cyclic GMP-AMP synthase-stimulator of interferon genes; TBHP, tertbutyl hydroperoxide; IDD, intervertebral disc degeneration; NMN, β-nicotinamide mononucleotide; NAD+, nicotinamide adenine dinucleotide; SOD, superoxide dismutase; PQ, paraquat; PI3K/Akt, phosphoinositide 3-kinase/Protein kinase B; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; OS, oxidative stress; LPS, lipopolysaccharide; NLRP3, NOD-like receptor family pyrin domain containing 3; AGEs, advanced glycation end-products; ER, endoplasmic reticulum; Nrf2, nuclear factor erythroid 2-related factor 2.

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Adapt, Mitigate, and Target: The Role of Oxidative Stress in Intervertebral Disc Homeostasis and Disc Degeneration
Neurospine. 2026;23(2):316-334.   Published online April 30, 2026
DOI: https://doi.org/10.14245/ns.26420332.0166
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Adapt, Mitigate, and Target: The Role of Oxidative Stress in Intervertebral Disc Homeostasis and Disc Degeneration
Neurospine. 2026;23(2):316-334.   Published online April 30, 2026
DOI: https://doi.org/10.14245/ns.26420332.0166
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Adapt, Mitigate, and Target: The Role of Oxidative Stress in Intervertebral Disc Homeostasis and Disc Degeneration
Image Image Image
Fig. 1. Adapt-Mitigate-Target framework of oxidative stress in intervertebral disc degeneration. Disc cells adapt to an extreme microenvironment through metabolic rewiring and redox homeostasis to maintain extracellular matrix integrity. Failure of these mechanisms leads to redox imbalance, mitochondrial dysfunction, inflammation, cellular senescence, and matrix degeneration. Therapeutic strategies aim to restore redox balance and target downstream degenerative pathways to potentially stabilize disc structure and function. AF, annulus fibrosus; ECM, extracellular matrix; NP, nucleus pulposus; ROS, reactive oxygen species; HIF-1/2, hypoxia-inducible factor 1/2; EV, extracellular vesicle.
Fig. 2. Schematic overview of redox homeostasis and redox imbalance in intervertebral disc degeneration. (A) Under physiological conditions, a balance is maintained between oxidant production and antioxidant defenses. Degenerative factors increase reactive oxygen species while antioxidant capacity declines, leading to redox imbalance and oxidative stress. This imbalance may be mitigated or restored through targeted biological and regenerative therapies. (B) The intervertebral disc relies on functional NP, AF, and CEP cells to maintain extracellular matrix homeostasis. Once a redox threshold is exceeded, oxidants and ROS, which are normally part of physiological signaling, trigger a cascade of cellular dysfunction, matrix degradation, and tissue damage that self-propagates and progressively deteriorates disc structure. AF, Annulus fibrosus; CEP, Cartilage endplates, ECM, Extracellular matrix; NP, Nucleus pulposus; ROS, reactive oxygen species.
Fig. 3. Simplified schematic of cellular redox balance and redox signaling in intervertebral disc cells. Reactive oxygen species (ROS) arise from mitochondrial electron transport chain activity and membrane associated NADPH oxidase (NOX2). Superoxide (O2·−) is converted to hydrogen peroxide (H2O2) by superoxide dismutases (SOD1, SOD2, SOD3), with H2O2 acting as both a signaling molecule and a source of oxidative stress after diffusion through aquaporins (AQPs). Antioxidant systems including catalase, glutathione peroxidases, peroxiredoxins, and the thioredoxin system detoxify ROS and preserve redox homeostasis. Excess ROS activate stress pathways such as ASK1 mediated JNK and p38 signaling, while redox-sensitive transcriptional programs including NRF2 and NF-κB coordinate cytoprotective or catabolic responses. The balance between these pathways determines cellular fate. ROS, reactive oxygen species; NOX2, NADPH oxidase 2; SOD, superoxide dismutase; GPx, glutathione peroxidase; PRx, peroxiredoxin; TRx, thioredoxin; TRxR, thioredoxin reductase; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2 related factor 2; NFκB, nuclear factor kappa B; IκB, inhibitor of nuclear factor kappa B; ASK1, apoptosis signal-regulating kinase 1; JNK, c-Jun N-terminal kinase; p38, p38 mitogen-activated protein kinase; GSH, reduced glutathione; GSSG, oxidized glutathione; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; NADP+, nicotinamide adenine dinucleotide phosphate, oxidized form; ATP, adenosine triphosphate; ETC, electron transport chain.

Fig. 1.

Fig. 2.

Fig. 3.

Adapt, Mitigate, and Target: The Role of Oxidative Stress in Intervertebral Disc Homeostasis and Disc Degeneration
Intervention Proposed mechanism of action Experimental models (exposure) Route of administration Key outcomes Translation status References
ROS scavengers
 GSH ROS scavenging Human NP and CEP cells (H2O2, IL-1̠) In vitro Reduced ROS levels, apoptosis, ECM catabolism, and CEP calcification Preclinical [84, 88]
 N-acetyl cysteine ROS scavenging Human NP and rat AF cells (H2O2, BSO, TNF-α, DMSO) Oral Reduced ROS levels, ECM catabolism, and inflammation Preclinical [78, 89]
Rat IVD puncture model (in vivo)
 Pyrroloquinoline quinone Mitochondrial dehydrogenase cofactor Rat NP cells (H2O2) In vitro Reduced ROS levels, ECM catabolism, and mitochondrial apoptosis Preclinical [56]
 Mitoquinone Mitochondria-specific antioxidant Human NP cells (Compression) In vitro Inhibited lipid peroxidation, maintained membrane potential, limited ROS and apoptosis Preclinical [63]
 Fullerols ROS scavenging Human NP cells (H2O2, IL-1β) Intradiscal Reduced ROS levels and inhibition of ECM degradation Preclinical [90]
Rabbit IVD puncture model (in vivo)
Pharmaceutical drugs
 Metformin cGAS-STING pathway Human and rat NP cells (TBHP) Intraperitoneal (rat) Attenuated senescence and apoptosis via p53/p21/Rb and p16/Rb axes Clinical (observational) [72, 91, 92]
Autophagy Rat IVD puncture model (in vivo) Oral (human)
p53/p21/Rb axes Human cohort (observational) Reduced IDD risk in diabetic patients
 Vitamin D PI3K/Akt activation Rat and mouse NP cells (H2O2, IL-1β) Intraperitoneal (mouse and rat) Counteracted OS, senescence, apoptosis, and ECM degradation; and promoted mitophagy Preclinical [93, 94, 95]
NF-κB inhibition Mouse tail suspension model and rat IVD puncture model (in vivo)
 NMN NAD+ precursor Human NP cells (PQ) Intraperitoneal Attenuated ROS and cellular senescence; reduced mechanical stress-induced IDD and pain Preclinical [4]
SOD2 activation Mouse tail-looping model (in vivo)
Hormones
 Melatonin PI3K/Akt activation Human and mouse NP cells, rat Intradiscal (rabbit and rat) Reduced ROS, apoptosis; enhanced autophagy and ECM homeostasis Preclinical [96]
NF-κB inhibition NP/AF/CEP cells (H2O2, IL-1β, TNF-α, TBHP, high glucose, LPS compression) Intraperitoneal (rat)
Rabbit IVD puncture model (in vivo)
Rat IVD puncture model and tail compression model (in vivo)
 Estrogen Antioxidant capacity Rat NP cells (IL-1β) Not specified Attenuated IL-1β–induced apoptosis and limited ECM catabolism Preclinical [81, 97]
Rat ovariectomized model (in vivo)
 Parathyroid hormone Sonic hedgehog pathway Human NP cells (IL-1β) Subcutaneous Increased SOD1/SOD2 expression, dampened inflammation and apoptosis, stimulated ECM synthesis Preclinical [98]
Mouse tail suspension model (in vivo)
Lifestyle interventions
 Weight and glucose control Systemic OS and NLRP3 inflammasome Human NP cells, rat AF cells (AGEs, high glucose) In vitro AGEs/high glucose promote OS and senescence; obesity amplifies OS and IDD Clinical (observational) [14, 77, 100]
Human (observational)
 Smoking cessation Exogenous ROS and ER stress Mouse EP cells (iron) Inhalational Cigarette smoking enhances OS through ER stress and mitochondrial dysfunction Clinical (observational) [6]
Mouse iron overload model (in vivo)
Mouse and rat cigarette smoke exposure model (in vivo)
Human (observational)
 Massage therapy Mechanical stimulation Rat IVD puncture with intradiscal TNF-α injection model (in vivo) Massage therapy Reduced mechanical allodynia and ROS levels; increased GSH and SOD expression Preclinical [101]
Biotechnologies
 Hydrogels Drug delivery system In vitro and in vivo Intradiscal implantation Enabled sustained release of antioxidant compounds mimicking NP properties Clinical (early phase) [102, 103]
Human (IVD herniation)
 Mesenchymal stromal cells Paracrine signaling In vitro and in vivo Intradiscal Exerted anti-catabolic and antioxidant effects; differentiation toward NP-like phenotype Clinical (early phase) [82]
Reconstituting NP homeostasis Human (discogenic pain)
 Extracellular vesicles Transportation of a broad range of bioactive molecules Human and rat NP cells (H2O2, IL-1β) Intradiscal Attenuated OS by reducing ROS and modulating SOD1, SOD2, and Nrf2 Preclinical [104, 105, 106]
Rat IVD puncture model (in vivo)
Table 1. Examples of therapeutic strategies targeting oxidative stress in intervertebral disc degeneration

ROS, reactive oxygen species; GSH, glutathione; NP, Nucleus pulposus; H2O2, hydrogen peroxide; IL-1β, interleukin-1β; CEP, cartilage endplate; ECM, extracellular matrix; AF, annulus fibrosus; BSO, buthionine sulfoximine; TNF-α, tumor necrosis factor-α; DMSO, dimethyl sulfoxide; cGAS-STING, cyclic GMP-AMP synthase-stimulator of interferon genes; TBHP, tertbutyl hydroperoxide; IDD, intervertebral disc degeneration; NMN, β-nicotinamide mononucleotide; NAD+, nicotinamide adenine dinucleotide; SOD, superoxide dismutase; PQ, paraquat; PI3K/Akt, phosphoinositide 3-kinase/Protein kinase B; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; OS, oxidative stress; LPS, lipopolysaccharide; NLRP3, NOD-like receptor family pyrin domain containing 3; AGEs, advanced glycation end-products; ER, endoplasmic reticulum; Nrf2, nuclear factor erythroid 2-related factor 2.

Table 1.

NS : Neurospine
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