Metabolite-Driven Immunometabolic Crosstalk in Intervertebral Disc Degeneration: The Macrophage-Disc Cell Interface

Abstract

Intervertebral disc degeneration (IVDD) is accompanied by extracellular-matrix disruption, metabolic stress and immune-cell infiltration, but how metabolites mediate communication between disc cells and macrophages remains incompletely defined. This narrative review examines lactate, succinate and kynurenine as candidate signalling metabolites at the macrophage-disc cell interface and proposes an integrative metabolite-centred framework. Evidence is strongest for lactate, which is supported by IVDD-specific studies linking glycolytic adaptation and impaired clearance to acidosis, MCT-dependent metabolic coupling, ASIC/NLRP3 activation, lactylation, cellular senescence and matrix catabolism. Evidence for succinate is more limited: IVDD-specific studies support SIRT5-AIFM1-dependent succinylation and mitochondrial dysfunction, whereas succinate accumulation and SUCNR1-mediated macrophage signalling in human degenerative discs remain unverified. The kynurenine-AhR axis is primarily hypothesis-generating; emerging IVDD-related observations implicate AhR and tryptophan-pathway changes, but a causal kynurenine-AhR macrophage-disc pathway has not been established. We propose that degenerating disc cells may reprogramme the local metabolic microenvironment, thereby altering macrophage functional states and creating a self-amplifying immunometabolic loop that feeds back on disc-cell injury and extracellular-matrix degradation. Future studies should combine spatial immunometabolomics in human tissue with cell-specific and causal intervention experiments to distinguish established mechanisms from context-dependent or extrapolated pathways and to evaluate potential microenvironment-directed therapeutic targets.

Introduction

Chronic low back pain is a major global cause of disability, affecting approximately 619 million people in 2020 and projected to increase further by 2050.¹ Intervertebral disc degeneration (IVDD) is a common structural finding and can contribute to discogenic pain, disc herniation and impaired spinal function; however, radiographic degeneration, discogenic low back pain and chronic low back pain are not interchangeable entities. Degenerative imaging findings can also occur in asymptomatic individuals.² Accordingly, this review uses IVDD to describe the structural and cellular degenerative process and refers separately to symptomatic or pain-related phenotypes when supported by the cited evidence.

Current management of symptomatic IVDD includes analgesics, exercise-based conservative care, interventional procedures and surgery. These approaches can improve pain and function but generally do not restore the normal cellular composition, extracellular matrix (ECM) architecture or biomechanical properties of a degenerated disc.^3,4 Regenerative strategies, including cell-based therapies, extracellular vesicles, biomaterials and gene-based approaches, are also being investigated, but their efficacy is constrained by the hostile and poorly vascularised disc microenvironment.⁴ These limitations motivate a mechanistic focus on the local metabolic and immune conditions that may sustain degeneration.

IVDD involves interacting processes rather than a single pathway. ECM degradation, inflammatory cytokine release, oxidative stress, cellular senescence, impaired autophagy and regulated cell-death programmes can reinforce one another: inflammatory mediators increase matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) activity, while mitochondrial damage and senescence promote a senescence-associated secretory phenotype that further amplifies inflammation and matrix loss.^5,6 Much of the literature nevertheless examines individual pathways or cell types in isolation, leaving the metabolic basis of intercellular communication less clearly defined.

Immunometabolism provides a framework for connecting these processes. Metabolic reprogramming can alter macrophage cytokine production, phagocytosis and inflammatory state, while inflammation can in turn reshape glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation and amino-acid metabolism.⁷ Metabolites such as lactate, succinate and kynurenine can therefore function as signalling mediators through transporters, receptors, ion channels and post-translational modifications rather than as passive metabolic end products.^7–9 Previous reviews have broadly summarised immune cells, inflammation and pharmacological immunometabolic regulation in IVDD.^10,11 The present review instead focuses on three signalling metabolites at the macrophage-disc cell interface and develops a testable model of bidirectional metabolite-driven crosstalk.

The intervertebral disc is particularly suited to this perspective because limited vascular supply exposes resident cells to hypoxia, nutrient restriction, acidity and diffusion-dependent waste clearance.¹² With degeneration, endplate dysfunction, matrix disruption and annular fissuring can further restrict transport, promote accumulation of damage-associated molecular patterns (DAMPs) and ECM fragments, and facilitate macrophage recruitment into or around damaged regions.^13,14 Macrophages are therefore positioned both to sense the altered metabolic microenvironment and to feed inflammatory, catabolic and reparative signals back to nucleus pulposus, annulus fibrosus and cartilaginous endplate cells.

We selected lactate, succinate and kynurenine because they represent three complementary levels of evidence and three distinct modes of metabolic signalling. Lactate has the strongest IVDD-specific evidence and directly links glycolysis, acidosis, monocarboxylate transport, acid sensing and lactylation. Succinate provides a mechanistic bridge between mitochondrial/TCA-cycle stress and inflammatory signalling, but direct evidence for succinate-succinate receptor 1 (SUCNR1) signalling in IVDD remains limited. Kynurenine extends the framework to inflammation-responsive amino-acid metabolism, aryl hydrocarbon receptor (AhR) signalling and neuroimmune regulation, while remaining largely hypothesis-generating in the disc context.^8,9,15

Accordingly, this article is a narrative review rather than a systematic review. Its aims are to synthesise established IVDD-specific findings, distinguish them from mechanisms supported mainly by animal/in vitro IVDD studies or extrapolated from other inflammatory and pain conditions, and use those evidence levels to generate testable hypotheses. Throughout the review, evidence is interpreted as (1) direct human IVDD evidence, (2) IVDD-specific animal or in vitro evidence, or (3) mechanistic evidence extrapolated from other fields. Context-dependent or conflicting observations, including macrophage responses to lactate and SUCNR1 signalling, are treated as such rather than as uniformly directional effects. On this basis, we propose that metabolic reprogramming in degenerating disc cells may reshape local metabolite pools, alter macrophage functional states and create a self-amplifying immunometabolic loop that contributes to inflammation, ECM degradation and pain-related remodelling.

The Immunometabolic Niche of the Intervertebral Disc

Metabolic Microenvironment of a Healthy Intervertebral Disc

The centre of the intervertebral disc is a nucleus pulposus (NP), surrounded by an annulus fibrosus (AF), and at both ends of the adjacent vertebrae are cartilaginous endplates (CEP).¹⁶ Given the lack of blood vessels in most parts, this anatomy is relatively metabolically inactive. Oxygen, glucose and other small solutes reach the disc cells by diffusion from the capillaries in the vertebral body and outer annulus, and the CEP serves as an important transport hub.^17,18 Therefore, disc cells live in a nutrient-depleted environment and need to obtain necessary solutes and eliminate metabolic waste in other ways.

NP cells in the disc cell population experience the most limited nutrient supply and metabolic conditions. They have a long diffusion distance and poor vascularisation, so they are oxygen- and glucose-deprived. Oxygen concentration in the NP is about 1%-5%, and the lactate level is relatively high.^19,20 Therefore, glycolysis will serve as the primary energy supply and oxidative phosphorylation will be relatively dormant. Hypoxia-inducible factor 1 alpha (HIF-1α) stability in NP cells is an oxygen-independent metabolic adaptation; it is constantly expressed even under normoxia, promotes glycolysis, and maintains matrix homeostasis by regulating aggrecan expression.^21,22 Therefore, the hypoxia in a healthy disc should not be considered pathologically significant; NP cells are adapted to this environment.

The disc microenvironment is also relatively hyperosmotic and slightly acidic. Abundant proteoglycans in the NP attract water to generate osmotic swelling pressure for load-bearing, and disc cells need to maintain osmotic balance.^23,24 Disc cells are highly dependent on glycolysis and thus continuously produce lactate. Lactate is mainly removed by diffusion, so the pH in the core of the NP is lower than in well-vascularised tissues.²⁵ The matrix is well-organised in a physiological state, so endplate transport is efficient and cell density is relatively low. Thus, the normal disc is better understood as a specialised hypoxic, glycolytic, hyperosmotic, and relatively immune-isolated tissue rather than a metabolically inactive one.

Another characteristic of the undamaged disc is an underlying immune-privileged state. Both the physical and molecular barriers are damaged to some extent. AF and CEP offer anatomical separation, and locally expressed immunoregulatory molecules provide molecular immunosuppression. Together, these mechanisms protect the core NP from the general immune system’s recognition and prevent direct contact between NP antigens and circulating immune cells.^26,27 Immune privilege is not absolute, so the state of homoeostasis must be maintained. Given the limited regenerative capacity and relatively weak anti-inflammatory effect of the disc, regulation of this must be stringent.

Immunometabolic Remodelling in the Degenerating Disc

The relatively stable microenvironment of the intervertebral disc degenerates gradually. CEP sclerosis and calcification restrict solute diffusion at the disc-vertebral junction, thus reducing oxygen and glucose supply and impairing lactate clearance.²⁸ Recently, studies have shown that CEP degeneration severely impairs metabolic transport and biomechanical response.¹⁹ Intraflagellar transport protein 88 (IFT88) is required to suppress IVDD by regulating CEP calcification,²⁹ and the leptin–osteocalcin (OCN)/HIF-1α axis promotes CEP calcification and ossification.³⁰ Matrix damage will change both the biochemical and mechanical environment of the disc. Loss of aggrecan and other proteoglycans reduces the water-binding capacity and osmotic pressure, thereby weakening the compressive load-bearing ability of the NP.^23,24 The above structural modifications are associated with metabolic stress; restricted nutrient diffusion and a lower matrix water content lead to the accumulation of metabolic waste. A 2025 goat study was the first to report in vivo measurements showing that both lactate and oxygen concentrations rise significantly in degenerated NP tissue.¹⁹

Another kind of change is inflammation in this period. When the extracellular matrix is damaged due to mechanical stress or other reasons, disc cells release more pro-inflammatory factors such as interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). These mediators activate matrix-degrading enzymes, suppress matrix synthesis, and thus induce cell death or senescence.^31,32 Lactate is no longer only produced by glycolysis under these conditions. Lactate accumulation and a low pH can further harm NP cells, promote catabolism, and create a microenvironment favourable to inflammatory signalling.^25,33 NP pH will be as low as approximately 6.8–6.5 during degeneration.²⁰

It is damaged, and the immune-isolated state of the disc is unstable. Annular fissures, endplate injuries and neovascularisation can serve as routes for immune cells to enter the disc.^34,35 Disc cells that have been damaged and stressed release DAMPs, such as high-mobility group box 1 (HMGB1) and S100 proteins, to actively promote an immune response by activating macrophages and other inflammatory pathways. Burt and others have shown that after disc injury, HMGB1 increases rapidly and remains at a high level for 28 days, attracting macrophages and modifying local tissue mechanics.³⁶ Macrophages are the most commonly studied immune cells in this context, although T cells, mast cells and other immune populations have also been reported in degenerated or herniated discs.^34,35 All these alterations to immune cell behaviour occur in a specific metabolic environment, such as a low-pH, lactate-rich, hypoxic, ECM-fragmented and inflammatory state. In turn, immune mediators inhibit disc-cell metabolism and matrix degradation.

Recently, scholars have found a kind of metabolic connection among these discs. The old idea was that lactate produced by glycolytic NP cells would be passively taken up at the endplate into the blood. A number of studies by the Risbud group have refuted this view. Monocarboxylate transporter 1 (MCT1) deletion at the endplate and annulus causes severe disc degeneration, including NP-cell loss, and structural alterations of the endplate. Metabolomics and transcriptomics have shown that MCT1-mediated lactate transport is required for the differentiation and maturation of endplate chondrocytes. Lactate also serves as a TCA cycle intermediate and regulates gene expression by modifying histones and non-histone proteins through lactylation. Therefore, it has been concluded that metabolic coupling of the disc spaces is required for disc growth and the maintenance of healthy tissue.³⁷

Over time, the above factors will damage the disc and cause continuous inflammation and metabolic stress. Therefore, the damaged disc should not be regarded solely as a place of mechanical injury but also as a metabolically impaired and immunologically active tissue microenvironment. Among the above specialists, macrophages are one of the first immune cells to respond to metabolic stress and inflammatory signals; thus, they link metabolic injury to damage in tissues.

Macrophages in IVDD: Central Cells of Immunometabolic Crosstalk

Macrophages are relatively abundant and highly active immune cells in the degenerated intervertebral disc. In a healthy disc, the NP is relatively isolated from systemic immune surveillance by the AF, CEP and local immunoregulatory mechanisms. Disruption of this barrier will no longer be considered an isolated tissue compartment. Annular fissures, endplate injuries and matrix ruptures can expose NP components to the host immune system, and thus peripheral monocytes are recruited to or near the disc via chemokine-dependent mechanisms.^14,26,38 Wang and others have extended this work to single-cell resolution. Single-cell RNA sequencing (scRNA-seq) of degenerative rat intervertebral discs has identified seven cell subsets, and leukocyte infiltration peaked on postoperative day 14.³⁹ Recently, some studies have shown that stressed NP cells are not passive. Under inflammatory stimulation, they release CCL2 and CCL7 via an integrated stress-response pathway, recruit CCR2-positive monocytes and macrophages, and promote pro-inflammatory activation.⁴⁰ Therefore, the accumulation of macrophages in IVDD may be due to both tissue damage and an active response by disc cells to the local stress via metabolic and inflammatory signals that recruit immune cells.

Macrophage migration to the disc is also associated with tissue injury. Fissures in the AF provide direct routes for immune cell invasion, and endplate injury and sclerosis impair nutrient supply and may form an inflammatory zone between the disc and vertebral bone marrow. Neovascularization frequently accompanies immune-cell infiltration and sensory nerve ingrowth. Macrophage polarisation in the outer AF of human cervical discs is related to disc degeneration and neural ingrowth; therefore, it is proposed that immune infiltration, vascular remodelling, and pain-related innervation may occur simultaneously in the same anatomical region rather than independently.⁴¹ Earlier human cadaveric studies have also shown that macrophage populations of different phenotypes accumulate and distribute in various ways after injury and degeneration.¹³ Macrophages are therefore not evenly distributed in the IVDD; their distribution is determined by the site of entry and local microenvironmental signals.

Macrophages in IVDD are generally divided into M1 and M2 types, but this two-category division cannot fully explain their behaviour in vivo. Although the M1/M2 model is more convenient for experiments, macrophages are more accurately regarded as a dynamic functional spectrum that responds to all sorts of local cytokines, oxygen tension, matrix fragments, mechanical stress and metabolites.⁴² Several recent systematic reviews have provided all-encompassing summaries of this area. Dou et al have investigated the role of macrophages in IVDD, the regulating mechanisms for regulating macrophage behaviour, and therapeutic strategies targeting macrophage regulation.¹⁴ Zheng and others have reported macrophage polarisation phenotypes, mechanisms of polarisation and strategies to target macrophage polarisation.⁴³ Another study has shown that the IVDD microenvironment, specifically hypoxia and acidity, alters macrophage function in ways that regulate the nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K-Akt) and nuclear factor erythroid 2-related factor 2 (NRF2) pathways of macrophage polarisation.⁴⁴ Macrophages have different functions at different times during degeneration. Early after annular rupture or NP exposure, they help clear cellular debris and matrix fragments. If the inflammatory stimulus continues, the immune response becomes chronic and fails to resolve; thus, IL-1β, TNF-α, IL-6, CCL2 and matrix-degrading enzymes are produced persistently. Therefore, the main problem is not whether macrophages are M1-type or M2-type, but rather which functional programmes are expressed at a given time and in a particular area under specific metabolic conditions.

Macrophage efferocytosis is the clearance of apoptotic cells and cellular debris that occurs during the resolution of inflammation and tissue repair. Prolonged inflammation and cell death in IVDD may inhibit efferocytosis, prevent spontaneous resolution, and thus enable harmful material accumulation. Recently, LGR6 has been shown to regulate IVDD by modulating macrophage efferocytosis.⁴⁵ Therefore, we have a new reason for the lack of spontaneous recovery in inflammation in IVDD and propose that enhancing macrophage efferocytosis may be a way to promote the resolution of inflammation.

Single-cell and spatially resolved technologies are starting to reveal this complexity. Single-cell transcriptomics of human degenerative discs reveals considerable cell heterogeneity and a complex network of intercellular communication. Based on the above, disc degeneration is a joint disease of resident disc cells and immune cells, not solely caused by changes in NP cells.⁴⁶ A multi-omics framework that integrates scRNA-seq, cell-cell communication analysis, exosome biology, machine learning and Mendelian Randomisation has identified an expanded SPP1+ osteopontin-positive macrophage subset in degenerated discs. Macrophages are close to the NP cells and communicate through an SPP1-centric ligand-receptor network. Exosomes from SPP1+ macrophages induce a catabolic state in NP cells, which includes aggrecan loss, downregulation of COL2A1, and the initiation of apoptosis; pQTL-anchored Mendelian randomization further supports that circulating SPP1 is causally associated with IVDD risk. Human intervertebral disc specimens show increased SPP1 expression in degenerated discs and an association with Pfirrmann grade.⁴⁷ Single-cell and transcriptomic studies of mechanically induced IVDD have also identified an increase in macrophages and pinpointed SPP1-related macrophage signalling as a possible cause of degeneration.⁴⁸ Collectively, the above data support a shift from simple marker-based classification to functional mapping of macrophage subsets in different regions of the disc, including the outer AF, fissure margins, endplate-adjacent areas, and painful neovascularised regions.

Macrophages regulate disc cells by releasing soluble cytokines, chemokines, extracellular vesicles and metabolic regulators. IL-1β and TNF-α inhibit anabolic matrix synthesis, induce MMPs and ADAMTS family members, reduce the expression of ACAN and COL2A1, and increase catabolic enzymes such as MMP3, MMP13 and ADAMTS5.³² IL-6 and CCL2 increase local inflammation and monocyte recruitment. These signals can cause apoptosis, senescence and other inflammatory cell-death programmes, such as pyroptosis, in NP cells. Oxidative stress and mitochondrial damage occur; therefore, ferroptosis-like injury is induced. Macrophage-derived extracellular vesicles also regulate the above. M1 macrophage-derived exosomes deliver LCN2 to NP cells, activate NF-κB signalling, promote p21/p53-associated senescence, increase MMP13 expression and reduce type II collagen, thus exacerbating ECM imbalance.⁴⁹ Exosomes released by anti-inflammatory macrophages can alleviate disturbances in ECM metabolism. Macrophage-disc cell communication will be either harmful or beneficial according to the state of macrophages and vesicle contents.

A 2025 study has discovered a new bidirectional regulatory loop between macrophages and NP cells. ACE regulates O-GlcNAc glycosylation of PSAP, suppresses CBL-dependent ubiquitination-mediated degradation, and thus stabilises the PSAP protein. Stabilised PSAP binds to G protein-coupled receptor 37 (GPR37) on macrophages and promotes polarisation into an anti-inflammatory M2 type via ERK/SMAD2/3 signalling. The M2 macrophages then release TGF-β, which acts via the PI3K/AKT pathway to promote PSAP-Sortilin-mediated trafficking in NP cells. Therefore, the ACE-PSAP-GPR37 axis has formed a bidirectional and mutually reinforcing regulatory loop that is required for disc homeostasis.⁵⁰ Another study in 2025 shows that the DPP4 inhibitor sitagliptin reduces IVDD by interrupting a pathogenic positive-feedback loop between macrophages and NP cells.⁵¹ In short, the above results show that macrophage-disc cell interactions form a network of two-way regulation rather than simple amplification of inflammation.

Macrophages are also closely associated with discogenic pain. Macrophage-derived inflammatory products, such as prostaglandin-related mediators, nitric oxide, NGF and other neurotrophic factors, can sensitise nociceptive pathways and promote nerve ingrowth into normally aneural disc regions.^52,53 COX-2/PGE2 signalling may connect inflammatory activation with pain sensitisation, and NGF and BDNF are closely related to neurovascular ingrowth and sensory nerve activation. Cheng and others have also discovered in their studies that macrophages are a kind of immune cell involved in the development of IVDD. Exposure to a degenerative microenvironment can induce an autoimmune response and damage of the dorsal root ganglia through inflammation.^54,55 Macrophage connections include structural disc injury, chemokine-driven immune cell recruitment, metabolic stress, ECM degradation, regulated cell death and pain. Therefore, they are necessary effector cells in the disc cell-macrophage immunometabolic loop and may also be therapeutic targets.

Lactate Axis: Acidosis, Inflammasome Activation, Lactylation and Macrophage Modulation

Evidence level: relatively strong IVDD-specific evidence, including human/clinical observations and experimental disc models. Lactate is an index metabolite of the intervertebral disc. Unlike most well-vascularised tissues, the disc depends on diffusion through the cartilaginous endplate (CEP) and peripheral annulus fibrosus (AF) for nutrient supply and waste removal. Nucleus pulposus (NP) cells are chronically exposed to low oxygen and rely heavily on glycolysis; this physiological glycolytic programme is not inherently pathological. Under physiological conditions, reported NP lactate concentrations are commonly in the low-millimolar range, and lactate can support metabolic coupling between disc compartments in addition to serving as a metabolic product.^15,33 As diffusion and transport capacity decline during degeneration, however, impaired lactate and proton clearance can convert this adaptive feature into a source of metabolic stress.

Lactate accumulation in IVDD reflects both increased production and impaired clearance. Hypoxia, inflammatory stimulation and mechanical stress can increase glycolytic flux, whereas sclerotic or calcified endplates can restrict solute diffusion between the disc and adjacent vertebral bodies.²⁸ Clinical and experimental studies report higher lactate levels in degenerative discs, together with reduced pH and adverse effects on proteoglycan/protein synthesis, oxidative stress and cellular senescence.^25,33,55,56 These observations support a concentration- and context-dependent effect rather than a universal threshold. Values of approximately 2–5 mM in physiological disc settings and values above 10 mM or several-fold increases in experimental degeneration have been reported, but the absolute concentration depends on tissue compartment, species or model, sampling method and disease stage.^33,55 Lactate should therefore be viewed as a physiological metabolite that becomes potentially pathogenic when production and retention exceed local buffering and clearance capacity.

A reason for lactate-acidosis damage in disc cells is the activation of acid-sensing ion channels (ASICs). An acidic environment activates the ASIC family, such as ASIC1a and ASIC3, which are expressed in disc-related cells and pain-sensitive neurons. ASIC activation increases cation influx and thus raises the intracellular concentration of Ca²⁺; therefore, too much calcium damages mitochondria, produces free radicals and injures cells. Acidic stimulation of NP cells activates ASICs and promotes NLR family pyrin domain containing 3 (NLRP3)-mediated pyroptosis. Inhibition of ASIC1a reduces inflammatory injury and pyroptosis; thus, acid sensing may be both a consequence of a low-pH environment and a cause of disc-cell damage.⁵⁷ Song and others have elucidated the mechanism of ASIC1a. ASIC1a-mediated Ca²⁺ influx provides a molecular basis for NP-cell pyroptosis under acidic conditions, and ASIC1a emerges as a regulatory target through which improvement of the inflammatory environment, reduction of NP-cell pyroptosis, modulation of anaerobic glycolysis, and reduction of lactate production may be interrupted.⁵⁸ A related study has found that with the progression of IVDD, the expression of ASIC1a is elevated; under acidic conditions, ASIC1a in nucleus pulposus stem cells (NPSCs) is upregulated, and the mitochondrial apoptotic pathway is triggered. ASIC1a suppresses the expression of SIRT3, disturbs mitochondrial redox homeostasis, exacerbates mitochondrial oxidative stress, and thus promotes apoptosis in human NPSCs and IVDD.⁵⁹ ASIC3 has also been identified as a treatment target for acidic disc degeneration and is related to pain and catabolic responses.⁶⁰ Lactate-derived acidification is thus upstream of calcium dysregulation, mitochondrial injury, inflammation and regulated cell death.

Another link in the pathway that promotes IVDD is the NLRP3 inflammasome. Acidic stress activates NLRP3; caspase-1 is then activated, and mature IL-1β and IL-18 are released. The above cytokines induce local inflammation, inhibit matrix synthesis and activate catabolic enzymes. Gasdermin D-mediated membrane pore formation leads to pyroptosis and releases more danger signals that extend inflammation. Lactate accumulation lowers pH; thus, acidic stress activates ASICs and NLRP3, increases inflammasome-derived IL-1β, and promotes ECM degradation and further metabolic stress. Xia and others have provided direct evidence for this mechanism by showing that increased lactate activates the NLRP3 inflammasome, worsens inflammation, and promotes NP-cell senescence through enhanced reactive oxygen species (ROS).⁵⁵ SOX4 promotes IVDD by activating the EZH2/NRF2 pathway in response to mitochondrial ROS-induced NLRP3 activation;⁶¹ overexpression of FOXO3a suppresses IVDD through inhibition of NLRP3-mediated pyroptosis];⁶² and obesity increases IVDD by activating the NLRP3 inflammasome in NP cells.⁶³ Other research on lactate has also found that changes in lactate metabolism can inhibit the activation of NLRP3, suppress inflammatory amplification, and improve the prognosis of experimental IVDD models.⁵⁵

Recently, studies have provided new basic information on the physiological function of lactate in intervertebral discs. The previous model assumed that the lactate released by glycolytic NP cells would be passively transported across the endplate into the bloodstream. A number of studies by the Risbud group have refuted this view. Endplate- and AF-specific MCT1 knockout mice have developed severe disc degeneration with NP-cell loss and endplate structural abnormalities. Metabolomics and transcriptomics show that MCT1 deficiency inhibits endplate chondrocyte differentiation. In addition, lactate serves as a necessary substrate for the TCA cycle and can regulate gene expression by modification of histones and non-histones (lactylation). These studies have provided the first in vivo evidence that a loss of MCT1-mediated lactate uptake in endplate cells delays endplate maturation and promotes disc degeneration. The Reasons are serious. NP-derived lactate partially promotes the differentiation of endplate cartilage towards vascularised subchondral bone during skeletal growth, and disruption of this process restricts nutrient exchange and availability, thus impairing homeostasis in other disc compartments.^37,64 Therefore, at physiological concentrations, lactate is not only the result of metabolism but also required for the coordinated regulation of metabolism and endplate formation in the disc space.

Lactylation is another mode of action for lactate in terms of signalling. Lactate is a substrate for lysine lactylation and has other functions in acidosis. Histone lactylation is a type of lactate-derived epigenetic modification that connects glycolysis to gene transcription.⁶⁵ Lactate is both a metabolic product and a regulator of gene expression. Recently, research has shown that lactylation regulates NP-cell senescence, oxidative damage, autophagy and matrix-associated proteins inIVDD. In 2024, a study indicated that glutamine supplementation suppressed glycolysis and lactate production, reduced AMPKα lactylation, promoted AMPK phosphorylation, induced autophagy, and inhibited NP-cell senescence.⁶⁶

Systematic analyses of lysine lactylation in NP cells have also shown that lactylation-related proteins and pathways are disturbed during disc degeneration.⁶⁷ SOD1 lactylation at lysine 123 reduces the enzymatic activity of SOD1, exacerbates oxidative damage, and activates p53-related damage in NP cells.⁶⁸ Recently, lactylation has been associated with ferroptosis. Single-cell RNA sequencing shows that NP cells in IVDD have increased glycolysis, and lactate promotes ferroptosis by upregulating ACSL4 and lactylation.^33,69 Therefore, lactate is associated with ferroptosis in these cells. Xu and others have comprehensively investigated that lactylation is a post-translational modification that works with metabolic reprogramming and ECM modification to regulate the development of IVDD, osteoporosis, osteoarthritis and spinal cord injury.⁷⁰ Multi-omics Mendelian Randomisation has also identified three lactylation-related genes that are causally associated with IVDD.⁷¹ Non-histone lactylation can thus alter the antioxidant system in IVDD.⁶⁸ Collectively, the above results indicate that lactylation is not a single path but a post-translational regulatory center for lactate accumulation related to oxidative stress, cellular senescence, ferroptosis and matrix disorganisation.

We do not know whether lactate is pro-inflammatory or anti-inflammatory in the environment of a degenerated disc. Lactate has Context-Dependent Effects on Macrophage Biology. Under some inflammatory conditions, lactate can promote the pathogenic macrophage programme and the release of DAMPs such as HMGB1 through lactylation-dependent mechanisms.⁷² Lactylation of histones also occurs at a later time in macrophage activation and regulates genes that control tissue repair and homeostasis.⁶⁵ Therefore, lactate should not be regarded as uniformly pro-inflammatory or anti-inflammatory. Excess lactate and a low pH can damage disc cells and cause inflammation; thus, the reaction of macrophages in a lactate-rich environment differs according to the stage of the disease, oxygen tension, cytokine environment, and transport capacity. Extended inflammation may also involve repair-associated programmes. Therefore, not all lactate needs to be cleared; some physiological lactate can support disc-cell adaptation and intercellular metabolic cooperation. A more suitable therapeutic target is pathological lactate overload, maladaptive lactylation and acid-induced immune activation, rather than general inhibition of lactate metabolism.

Lactate is also produced in the degenerated disc through other means. It is an acidic-stress signal that relates to the inflammasome; it serves as a substrate for epigenetic and post-translational modifications, and changes macrophage behaviour through altered metabolism. Lactate supports endplate formation and disc health in a physiologically relevant manner by engaging MCT1. Pathologically, it leads to degeneration by inducing ASIC-mediated acidosis, activating the NLRP3 inflammasome and causing harmful lactylation. Thus, the lactate axis can help explain how impaired endplate diffusion, hypoxic glycolysis, acidosis, regulated cell death, matrix catabolism and immune-cell activity are interconnected in IVDD.

Succinate Axis: The SUCNR1–HIF-1α–NLRP3 Hypothesis in IVDD

Evidence level: limited IVDD-specific evidence. Experimental IVDD studies support a role for SIRT5-dependent protein succinylation and mitochondrial homeostasis, whereas direct demonstration of succinate accumulation, SUCNR1 expression patterns and succinate-driven macrophage signalling in human degenerative discs remains lacking. The succinate-SUCNR1-HIF-1α-NLRP3 pathway discussed below is therefore presented as a mechanistically plausible, testable hypothesis informed partly by evidence from other inflammatory systems. Succinate is a tricarboxylic acid (TCA)-cycle intermediate that can also act as an immunometabolic signal; in LPS-stimulated macrophages, succinate accumulation stabilises HIF-1α and increases IL-1β production.⁸

Succinate regulates inflammation in the two ways shown below. Intracellular succinate accumulates to inhibit prolyl hydroxylases, stabilise HIF-1α and promote the glycolytic transcriptional program and IL-1β production.^8,73 Extracellular succinate can also signal via succinate receptor 1 (SUCNR1), also known as GPR91, a G protein-coupled receptor expressed in both immune and non-immune cells.⁷⁴ Extracellular succinate released by activated macrophages in models of inflammatory arthritis signals through GPR91 to promote macrophage-mediated inflammation.⁷⁵ Other studies have found that SUCNR1 is involved in inflammasome priming and IL-1β-mediated inflammation.⁷⁶ SUCNR1 signalling is not uniformly pro-inflammatory; otherwise, the activation of macrophages in some states would be linked to anti-inflammatory or type 2-like programmes.⁷⁷ In 2026, a review paper has proposed that SUCNR1 is a metabolic signal integrator rather than a typical pro-inflammatory or anti-inflammatory receptor. Functional output is dictated by G-protein preference, such as Gi and Gq coupling, subcellular receptor distribution in endosomal regions, and an ebb-and-flow adjustment of intracellular and extracellular succinate pools. SUCNR1 associates with both Gi and Gq proteins. Abundant extracellular glutamine increases TCA cycle flux and basal succinate levels to suppress Gq signalling and promote receptor endocytosis. After activation, SUCNR1 quickly moves to endosomes, and Gi signalling remains at both the plasma membrane and endosomes; Gq can be recruited to late endosomal compartments. Macrophages have produced more succinate through glycolysis in the case of M1-like cells; additionally, M2-like cells express SUCNR1 at the plasma membrane. Succinate released by M1-like cells activates SUCNR1 on M2-like cells and promotes IL-1β secretion via Gi signalling.⁷⁸ Therefore, the effects of the succinate–SUCNR1 axis will differ depending on the type of cell, receptor distribution, inflammatory stimuli and metabolic status, and thus may have a dual function in IVDD.

The first possible applications of succinate for IVDD are based on the hypoxic disc microenvironment and mitochondrial stress. NP cells are in a low-oxygen environment and use HIF-1α signalling, but degeneration also causes nutrient deprivation, accumulation of acidic waste, oxidative stress and abnormal mechanical loading. Mitochondrial dysfunction is now known to be one of the causes of IVDD; it increases ROS production, damages mitochondrial quality control, and thus promotes cell death and ECM degradation.^79,80 Recently, studies have shown that mitochondrial morphology needs to be preserved for metabolic homeostasis in NP cells. Loss of OPA1 changes mitochondrial structure and TCA-related metabolite flux, promoting age-associated disc degeneration in mice.⁸¹ The above results do not directly show an increase in succinate within damaged human discs; instead, they suggest that TCA cycle metabolism has been disturbed by stress in disc cells and may promote degeneration.

IVDD-specific evidence for succinate-related post-translational regulation is beginning to emerge, but it should be distinguished from direct evidence of free succinate accumulation or SUCNR1 signalling. A 2023 study found reduced expression of the desuccinylase SIRT5 in rat NP tissue under mechanical stress. SIRT5 overexpression reduced mechanical injury-induced apoptosis and NP-cell dysfunction, whereas SIRT5 deficiency increased AIFM1 succinylation, disrupted AIFM1-CHCHD4 interactions, reduced electron-transport-chain subunits and worsened experimental IVDD.⁸² Subsequent work implicated EP300 in the regulation of SIRT5, autophagy and NP-cell protection.⁸³ Together, these findings provide IVDD-specific animal and cellular evidence that altered protein succinylation and SIRT5-dependent mitochondrial homeostasis can contribute to degeneration.^82,83 They do not, however, establish increased succinate concentration or a causal succinate-SUCNR1 pathway in human disc tissue.

The second is inflammatory macrophage biology as the supporting evidence. Macrophages are recruited to the annular fissures, endplate-adjacent areas and sites of neovascularisation during IVDD. These areas are hypoxic, have elevated lactate and matrix fragments, DAMPs and inflammatory cytokines, and all promote a switch to glycolysis and inflammatory metabolic reprogramming. Similar remodelling occurs in other inflammatory diseases, and succinate accumulation, HIF-1α stabilisation and increased IL-1β production are also present.^8,75 A plausible but unvalidated hypothesis is that disc injury recruits macrophages, the degenerative niche reprograms macrophage metabolism, succinate-associated HIF-1α signalling enhances IL-1β production, and IL-1β then accelerates disc-cell catabolism and matrix loss.^32,84 There is no direct evidence of succinate accumulation in IVDD macrophages; however, this biological pathway is mechanistically plausible and testable.

NLRP3 inflammasome is also one of the reasons. NLRP3 activation is frequently associated with IVDD, NP-cell pyroptosis, IL-1β maturation, and inflammatory ECM degradation.^85,86 Succinate enhances HIF-1α-dependent IL-1β expression and SUCNR1-related inflammasome priming in other inflammatory states; therefore, it may be upstream of NLRP3-mediated inflammatory amplification. Succinate is not the sole activator of the inflammasome in this model. It may be that ROS and mitochondrial injury have caused ionic imbalance, acidic stress and DAMPs; therefore, caspase-1 is activated, IL-1β/IL-18 is matured, and gasdermin-mediated pyroptosis occurs. The above mechanism is especially suitable for IVDD because all kinds of metabolic stress occur simultaneously in the same poorly vascularised area.

The lactate and succinate axes may converge on HIF-1α, but this interaction remains unverified in IVDD. Succinate can inhibit prolyl hydroxylases and stabilise HIF-1α in inflammatory macrophages,⁸ while lactate can influence HIF-1α regulation through related metabolic mechanisms. In a hypoxic and lactate-rich degenerative disc, altered TCA-cycle metabolites could therefore modify HIF-1α-dependent glycolytic and inflammatory programmes. This proposed synergy is mechanistically plausible but should be considered hypothesis-generating until succinate concentrations, cellular sources and causal effects are directly measured in IVDD models and human tissue.

Succinate is probably related to discogenic pain. Painful IVDD includes matrix degradation, release of inflammatory mediators, sensory nerve infiltration and neuroimmune alterations. Broader research on pain links altered cellular energy metabolism to nociceptive sensitisation, and succinate/SUCNR1 signalling has been proposed as a mediator of inflammatory pain.⁸⁷ GPR91 and other metabolite receptors are also involved in axonal growth and neural responses, so TCA-cycle-derived metabolites may affect pathological neural remodelling.⁸⁸ At present, no direct evidence has been found linking succinate to discogenic pain, dorsal root ganglion (DRG) sensitisation or neurovascular invasion in IVDD. Therefore, the above possibilities should be viewed as open and testable scientific questions rather than established mechanisms.

A 2026 network pharmacology study has provided additional indirect evidence linking succinate to IVDD. Based on a gut microbiota-metabolite-target network, a study has identified succinate as a key microbiota-derived metabolite linked to IVDD.⁸⁹ Therefore, it can be speculated that gut microbial succinate may affect the disc microenvironment by distributing systemically and provide metabolite-level support for the gut-disc axis. However, this hypothesis has not been supported by IVDD models.

In short, the succinate axis is still an emerging and unconfirmed mechanism of IVDD. Direct evidence of succinate accumulation in macrophage-disc cell crosstalk of human degenerative discs is scarce. Succinate is still associated with IVDD through several mechanisms, such as succinylation, regulation of mitochondrial homeostasis by the SIRT5/AIFM1 axis;^82,83 SUCNR1 signalling, where the receptor acts as a metabolic signal integrator to alter macrophage behaviour;⁷⁸ and HIF-1α stabilisation, which may work in concert with lactate to promote inflammation.⁸ Together, these pathways may be linked to mitochondrial dysfunction, inflammatory macrophage activation and IL-1β-mediated disc-cell catabolism. In the future, one will quantify succinate in human disc tissues, map SUCNR1 expression in NP cells, AF cells, endplate cells and macrophage subsets, and determine whether pharmacological or genetic modulation of this axis reduces inflammation, pyroptosis and ECM degradation in IVDD models.

The Kynurenine Pathway: A Possible Tryptophan–Kynurenine–AhR Axis in IVDD

Evidence level: hypothesis-generating, with limited IVDD-specific support. A causal kynurenine-AhR macrophage-disc pathway has not yet been established, so evidence from IVDD-related AhR expression, tryptophan-pathway changes and pain observations is distinguished below from mechanisms extrapolated from immunology and neuroinflammation. Tryptophan is converted to kynurenine through indoleamine 2,3-dioxygenase 1/2 (IDO1/IDO2) and tryptophan 2,3-dioxygenase (TDO/TDO2). Kynurenine can then be metabolised by KMO, KYNU and kynurenine aminotransferases to bioactive products including 3-hydroxykynurenine, quinolinic acid and kynurenic acid.^90,91 Across tumour immunity, neuroinflammation, chronic pain and autoimmune disease, kynurenine-pathway metabolites can regulate immune tolerance, oxidative stress, neuronal excitability and cell fate.^9,91–94 These cross-disease data provide biological rationale, but not direct proof, for an analogous pathway in IVDD.

The kynurenine pathway is increasingly studied in musculoskeletal and age-related disorders, and inflammatory cytokines relevant to IVDD may induce IDO1-dependent tryptophan catabolism.^32,95,96 A 2025 network-pharmacology and bioinformatics study identified AHR among candidate regulators of lumbar disc degeneration and reported higher AHR expression in degenerated disc tissue with associations to degeneration severity and mast-cell infiltration.⁹⁷ These findings provide IVDD-specific evidence for altered AhR biology. Importantly, they do not demonstrate that kynurenine is the upstream AhR ligand responsible for these changes, so they support investigation of the kynurenine-AhR axis rather than establish it as a confirmed IVDD mechanism.

Some immunomodulatory effects of kynurenine are mediated by AhR.^9,93 AhR is a ligand-activated transcription factor that can respond to endogenous metabolic signals, microbiota-derived molecules and environmental stimuli by altering gene expression in the immune-inflammatory system, redox homeostasis and cell fate.^94,98 Kynurenine is an endogenous agonist of AhR that activates the downstream pathway for immune tolerance and tumour immune evasion, as well as T-cell differentiation.^9,93 AhR expression and its functions have been studied in many kinds of immune cells, such as macrophages, dendritic cells, and T cells, and it regulates the signalling of cytokine production, cell differentiation, and inflammation.^94,99 Pharmacologically, Sawa and others have identified kynurenic acid as a downstream product of kynurenine that regulates cytokine and chemokine release by THP-1-derived macrophages via the AhR and GPR35 pathways.¹⁰⁰ Therefore, this has been directly linked to a kynurenine-metabolite-AhR-macrophage functional axis. Kynurenine binds to AhR and increases the transcription of canonical AhR target genes, such as CYP1A1, and under certain cellular conditions, immunoregulatory factors such as IDO1 and IL-10 are also upregulated. The above observations suggest a possible IDO1-kynurenine-AhR feedback loop that regulates tryptophan metabolism and immune function.^9,94,101

AhR activation can regulate macrophage inflammatory programmes, including IL-10 expression and phenotype-associated functions, in non-disc immune models.^99,101 Macrophages also infiltrate degenerating discs and influence inflammatory signalling and ECM metabolism.¹⁰² A testable hypothesis is therefore that, if kynurenine concentrations or flux are altered in the degenerative disc, kynurenine-AhR signalling could modify macrophage function and secondarily affect disc-cell catabolism. However, the complete kynurenine-AhR-macrophage-ECM pathway has not been experimentally demonstrated in IVDD, and its direction of effect may depend on cell type, disease stage and metabolite profile.

The Kynurenine Pathway may also be involved in pain and neuroimmune regulation. Research on chronic and neuropathic pain has discovered that kynurenine-pathway metabolites can change neuronal excitability, glial activation and nociceptive transmission.^103,104 Downstream metabolites, such as 3-hydroxykynurenine and quinolinic acid, may be involved in pronociception, and quinolinic acid can alter excitability via NMDA receptor-related pathways.¹⁰³ Celik et al have provided direct human evidence in a 2025 clinical observational study. A total of 37 patients with lumbar disc herniation underwent surgery, and seven tryptophan metabolites were quantified by LC-MS/MS. Quinolinic acid levels are positively associated with 24-hour postoperative VAS scores. Kynurenic acid and xanthurenic acid are also significantly altered perioperatively. Based on the above, some tryptophan metabolites, such as quinolinic acid, may be related to the degree of postoperative pain and are thus potential biomarkers for pain assessment.¹⁰⁵ Discogenic pain in IVDD is associated with inflammatory mediators, immune-cell infiltration, vascular ingrowth and nerve-fiber ingrowth.³¹ Thus, the kynurenine pathway may be a connection between amino acid metabolism, local immune inflammation and neuroimmune sensitisation. Direct evidence that kynurenine or its downstream products regulate discogenic pain, dorsal root ganglion neuronal excitability, or nerve-fiber ingrowth in degenerated discs has not yet been obtained. Therefore, the above mechanism should be regarded as a future research direction rather than an established path for IVDD-related pain.

Kynurenine metabolism may also intersect with the gut–disc axis. Gut microbiota modify host tryptophan utilisation and regulate AhR signalling and immune function via the kynurenine pathway, the serotonin pathway, and microbiota-derived indole metabolites.¹⁰⁶ The concept of a gut-disc axis has also been proposed, and gut dysbiosis may affect IVDD and low back pain through systemic inflammation, immune regulation and metabolic changes.¹⁰⁷ A 2025 Mendelian Randomization study has provided genetic evidence for a causal relationship by systematically examining the connections among gut microbiota, 1400 blood metabolites and IVDD.¹⁰⁸ Another IVDD animal study combining gut microbiome profiling and serum metabolomics reports changes in multiple circulating metabolites, including kynurenine and 5-hydroxyindoleacetic acid (5-HIAA), indicating that tryptophan-related metabolism may be involved in gut-disc metabolic crosstalk.¹⁰⁹ Thus, alterations in the gut microbiota may affect the whole-body and local concentrations of kynurenine, thus changing inflammation, oxidative stress and nociception at the periphery. Although the entire connection among gut microbiota, tryptophan/kynurenine metabolism, AhR and IVDD has not been fully verified, this system offers a feasible foundation for research on the intersection of systemic and local tryptophan catabolism.

Compared with lactate, the kynurenine pathway remains substantially less established in IVDD. Current IVDD-related observations include altered AhR expression in degenerated disc tissue,⁹⁷ induction of tryptophan-pathway enzymes under inflammatory conditions,¹¹⁰ associations between selected tryptophan metabolites and postoperative pain after lumbar disc herniation,¹⁰⁵ and broader genetic/metabolomic evidence linking gut microbiota and circulating metabolites with IVDD.^108,109 These findings are supportive but do not establish a causal kynurenine-AhR pathway in disc degeneration. Key unanswered questions include whether kynurenine and downstream metabolites are altered within human NP, AF and CEP tissue; which resident or immune cells express IDO1/TDO2/KMO/KYNU; whether AhR activation is protective, pathogenic or biphasic; and whether pathway-specific intervention changes ECM homeostasis, inflammation or nociception. Integrated metabolomics, single-cell/spatial profiling and causal intervention experiments are therefore required before therapeutic conclusions can be drawn.

To summarize the current evidence for these metabolite-related axes, Table 1 shows the direct IVDD evidence, macrophage evidence, disc-cell evidence, therapeutic potential and overall evidence strength of lactate, succinate, kynurenine and macrophage-mediated crosstalk.

Table 1.

Current Evidence for Lactate, Succinate and Kynurenine in IVDD

Axis	Direct IVDD Evidence	Macrophage Evidence	Disc-Cell Evidence	Therapeutic Potential	Evidence Tier	Refs
Lactate axis Lactate–MCTs ASIC/NLRP3 Lactylation	Direct evidence is relatively strong. The adult disc is avascular and depends heavily on glycolysis; lactate and low pH directly affect proteoglycan and protein synthesis in disc tissue. Degeneration is associated with altered intradiscal lactate and oxygen distributions, and impaired endplate transport may further limit metabolite clearance. Acidic, lactate-rich conditions activate ASIC signalling and NLRP3-related inflammatory injury in nucleus pulposus cells. Recent studies further link lactate accumulation and lactate-derived lactylation to nucleus pulposus cell senescence, oxidative stress, autophagy inhibition, impaired antioxidant defense, and ECM imbalance.	Macrophage-specific evidence in IVDD is still developing, but the mechanism is biologically plausible and supported by inflammatory macrophage studies. Lactate can alter macrophage function through acid stress, MCT-mediated transport, and lactylation-dependent gene regulation. In degenerating discs, macrophages are exposed to lactate, ROS, ECM fragments, and inflammatory cytokines; depending on disease stage and local pH, this environment may sustain inflammation or support later repair programs.	Disc-cell evidence is strong. Lactate and low pH suppress matrix biosynthesis; acid stress activates ASIC/NLRP3 signalling; and lactate-related signalling promotes nucleus pulposus cell senescence and oxidative injury. Studies of lactylation suggest that AMPKα, SOD1, and other non-histone targets connect glycolytic lactate with autophagy, ROS defense, senescence, oxidative injury, and ECM metabolism.	High translational potential. Candidate strategies include modulating pathological LDHA activity rather than completely blocking glycolysis, rebalancing MCT1/MCT4 transport, using pH-buffering or lactate-scavenging hydrogels, inhibiting ASIC1a/ASIC3 or NLRP3, and precisely targeting harmful lactylation events. Local biomaterial delivery is preferable because the disc is poorly vascularized and physiologically glycolysis-dependent. Treatment should therefore correct pathological lactate overload, acidosis, and maladaptive lactylation without suppressing basal glycolysis.	Strong — direct human/IVDD and experimental IVDD evidence.	[19, 25, 56, 57, 65, 66, 68]
Succinate axis Succinate–SUCNR1/GPR91 HIF-1α–NLRP3	Direct IVDD evidence is limited. Succinate has not been consistently quantified in human degenerative discs, and the expression of SUCNR1 in NP, AF, CEP cells, and disc-infiltrating macrophages remains unclear. The rationale mainly derives from IVDD-associated mitochondrial dysfunction and TCA-cycle stress, together with strong evidence from inflammatory macrophages that succinate stabilises HIF-1α and promotes IL-1β production.	Moderate indirect evidence shows that succinate accumulation is a canonical immunometabolic signal in inflammatory macrophages and supports HIF-1α-dependent IL-1β expression. Extracellular succinate can also signal through SUCNR1/GPR91 in macrophage-driven inflammatory disease models. Succinate is therefore a plausible amplifier of macrophage-mediated IL-1β, TNF-α, and NLRP3 signalling in IVDD, although this has not been directly demonstrated in disc tissue.	Disc-cell evidence is indirect. IVDD is closely associated with mitochondrial dysfunction, ROS accumulation, impaired mitochondrial quality control, and NLRP3 activation.80,86 These processes may disturb TCA-cycle intermediates, including succinate, but the direction, cellular source, and functional relevance of succinate changes in NP, AF, and CEP cells remain unresolved and require direct metabolite quantification.	Emerging therapeutic hypothesis. Candidate approaches include SUCNR1 antagonism, modulation of HIF-1α/IL-1β signalling, SDH/FH-related metabolic correction, enhancement of mitochondrial quality control, ROS control, and NLRP3 inhibition. Before translation, studies should first establish succinate accumulation, identify SUCNR1-positive cell types, and demonstrate causality in IVDD models.	Limited — IVDD preclinical evidence for succinylation/mitochondrial homeostasis; SUCNR1 macrophage signalling is largely extrapolated.	[8, 75, 80, 86]
Kynurenine axis Tryptophan–IDO1/TDO Kynurenine–AhR	Direct IVDD evidence is weak and novel. The kynurenine pathway has not been established as a dominant metabolic pathway in degenerative discs. Its inclusion is hypothesis-driven: IL-1β-, TNF-α-, and IFN-γ-related inflammatory cues in IVDD may induce IDO1/TDO-mediated tryptophan catabolism, whereas kynurenine can act as an endogenous AhR ligand.	Macrophage evidence is indirect but relevant. Kynurenine/AhR signalling regulates immune tolerance, T-cell responses, macrophage polarisation, oxidative stress, and inflammatory resolution in cancer, autoimmunity, and neuroinflammation. In IVDD, this pathway may modulate macrophage function within a cytokine-rich, hypoxic, and acidic niche, but definitive evidence for specific macrophage subsets is not yet available.	Disc-cell evidence is currently sparse. Potential targets include AhR signalling in NP, AF, and CEP cells, induction of IDO1 under inflammatory stress, and downstream effects of kynurenine metabolites on ROS, senescence, ECM metabolism, and neuroimmune signalling. These remain testable hypotheses rather than established IVDD mechanisms.	Exploratory potential. IDO1/TDO inhibitors, AhR modulators, KMO inhibitors, and microbiota-based regulation of tryptophan metabolism should be considered only after determining whether the kynurenine axis is protective, pathogenic, or biphasic in IVDD. Tryptophan, kynurenine, kynurenic acid, quinolinic acid, and the kynurenine/tryptophan ratio may first serve as candidate biomarkers.	Hypothesis-generating — limited IVDD-related AhR/tryptophan evidence; the causal kynurenine-AhR macrophage-disc pathway is unverified.	[9, 93, 111]
Macrophage crosstalk Disc cell–macrophage Immunometabolic loop	Direct IVDD evidence is strong. Human and experimental studies show macrophage accumulation in degenerated or injured discs, especially near AF fissures, endplate-adjacent regions, and neovascularized areas. Recent evidence indicates that stressed nucleus pulposus cells release CCL2/CCL7 and recruit CCR2-positive macrophages through an integrated stress-response pathway. Single-cell studies further support immune-cell heterogeneity and intercellular communication in IVDD.	Strong evidence. Macrophages secrete IL-1β, TNF-α, IL-6, CCL2, MMPs, and EV cargoes that reshape the disc inflammatory niche. M1 macrophage-derived exosomes promote nucleus pulposus cell senescence and ECM imbalance through LCN2/NF-κB signalling. Recent transcriptomic analyses also link SPP1-related macrophage signalling and macrophage polarisation signatures to degenerative progression.	Strong disc-cell evidence. Macrophage-derived cytokines suppress ACAN/COL2A1 synthesis, induce MMP3/MMP13/ADAMTS activity, and promote nucleus pulposus cell apoptosis, pyroptosis, ferroptosis, and senescence. Disc cells reciprocally regulate macrophages through CCL2/CXCL8, DAMPs, ECM fragments, lactate, ROS, and acidic stress, forming a feed-forward inflammatory-metabolic circuit.	High therapeutic potential. Strategies include moving beyond the M1/M2 binary toward functional macrophage states, reducing non-resolving glycolytic inflammation, promoting efferocytosis and resolution phenotypes, blocking chemokine-mediated recruitment, and locally delivering engineered EVs, macrophage-derived sEVs, nanoparticles, or immunomodulatory hydrogels. dECM hydrogels carrying M2 macrophage-derived sEVs represent a regenerative immunomodulatory approach supported by experimental IDD models.	Strong — human and experimental IVDD evidence; metabolite-specific macrophage phenotypes still require validation.	[13, 40, 46, 48, 49, 112]

Abbreviations: AF, annulus fibrosus; CEP, cartilaginous endplate; ECM, extracellular matrix; IVDD, intervertebral disc degeneration; MCT, monocarboxylate transporter; NP/NPC, nucleus pulposus/nucleus pulposus cell; ROS, reactive oxygen species; SUCNR1, succinate receptor 1.

Integrated Model: How the Lactate, Succinate and Kynurenine Axes May form a Degenerative Immunometabolic Loop

The three metabolic axes mentioned above are unlikely to be independent paths in IVDD. Age-related mechanical damage and overload cause endplate injury and other issues in the metabolic environment of the tissue. Over time, the disc will be organised as a tissue and develop an autonomous immunometabolic system. Ageing reduces the quality of the matrix, repeated abnormal loading, smoking, obesity and diabetes can all damage the disc through increased oxidative stress, impaired nutrient supply and altered cell metabolism.^113,114 At the same time, sclerosis or calcification of the CEP reduces oxygen and glucose diffusion and impairs the clearance of acid-producing metabolites. Therefore, the disc may be in a state of physiological hypoxia and has become pathologically nutrient-deprived and waste-retaining.¹¹⁵ The above reasons will also harm the ECM and create a metabolic environment that promotes the interaction of resident disc cells and immune cells.

Initiation of the Loop: Metabolic Stress and Disc-Cell Reprogramming

NP cells are the start nodes of this loop. Glycolysis supports the normal function of NP cells under hypoxia; however, in degeneration, impaired diffusion, inflammatory cytokines and mechanical stress all increase the demand for glycolysis, promote lactate production, and reduce extracellular pH.¹¹⁶ Acidosis thus exacerbates mitochondrial dysfunction, calcium dysregulation, oxidative stress and inflammasome activation. Mitochondrial damage alters the cell’s redox environment and inhibits the TCA cycle. Recently, research on the discs and cartilages of the body has discovered that mitochondria actively regulate to maintain metabolic homeostasis. Therefore, disruption of mitochondrial fusion promotes age-related disc degeneration.⁸¹

Research in 2025 has also identified reasons for metabolic change under mechanical stress. Mechanical stress activates PIEZO1, causes intracellular Ca²⁺ overload, triggers endoplasmic reticulum stress and a burst of mitochondrial ROS, and directly activates the NLRP3 inflammasome/NF-κB axis to promote release of pro-inflammatory mediators such as IL-1β. Energy metabolism subsequently declines. Excess ROS activates excessive mitophagy via the PINK1/Parkin pathway, and defective SIRT1 function further impairs mitochondrial quality control. ROS also links mitophagy with p53 signalling. Oxidative injury activates ATM/ATR kinases, promotes p53 phosphorylation, induces p21-mediated cell-cycle arrest, and at the same time, p53 suppresses SIRT1 expression and exacerbates mitochondrial dysfunction. This establishes a p53–ROS–mitophagy amplification circuit.¹¹⁷

Direct evidence of succinate accumulation in human degenerative discs is scarce. Rearrangement of the TCA cycle can be employed to ascertain whether succinate promotes the inflammatory response in stressed NP cells and infiltrating macrophages. Zhou and others carried out a non-targeted metabolomics study to examine changes in TCA cycle metabolites in patients with iatrogenic ischaemic damage.¹¹⁸

Amino acid metabolism can also be added to this system. Pro-inflammatory cytokines in the degenerative disc microenvironment may alter amino acid metabolism of NP cells through inflammatory stimulation. Direct evidence shows that IL-1β significantly upregulates IDO1 and KYNU in NP cells, thus activating the tryptophan-kynurenine pathway.¹¹⁰ However, there is still no strong evidence that this axis is a primary cause of IVDD, and a full causal relationship between IDO1–kynurenine–AhR signalling and the disease has not been demonstrated. Kynurenine and its downstream products regulate the AhR-dependent immune program, redox homeostasis and neuroimmune signals, so this pathway is worth exploring further in degenerated NP cells. Metabolic reprogramming in NP cells should therefore not be reduced to increased glycolysis alone. Increased glycolysis produces and accumulates lactate; mitochondrial dysfunction disrupts the TCA cycle and intermediate-metabolite homeostasis; and inflammatory stimulation can also alter amino acid pathways, such as tryptophan-kynurenine metabolism.

Amplification of the Loop: Macrophage Recruitment and Metabolic Reprogramming

The third is macrophage recruitment in the degenerative pathway. Injured or stressed NP cells release chemokines and danger signals to attract peripheral monocytes and macrophages. Recently, studies have shown that inflammatory stress activates the TLR4–mitochondrial ROS–dsRNA integrated stress-response pathway in NP cells, resulting in CCL2/CCL7 production, CCR2-dependent macrophage infiltration, and pro-inflammatory polarisation.⁴⁰ CXCL8/CXCR2 signalling may also promote NP-cell apoptosis and oxidative stress via NF-κB. Therefore, chemokine networks are associated with the recruitment of immune cells and directly cause disc cell injury.¹¹⁹

A 2025 study has provided direct experimental evidence for a positive feedback loop in which senescent NP cells promote M1 macrophage polarisation, and M1 macrophages further accelerate NP-cell senescence. Senescent NP cells promote macrophage polarisation into the pro-inflammatory M1 state in co-culture. Conversely, conditioned medium from M1 macrophages exposed to senescent NP cells enhances the senescence of healthy NP cells. This mutual influence constitutes a full-blown pathogenic cycle in which senescent NP cells promote M1 polarisation and M1 macrophages further accelerate NP-cell senescence.¹²⁰ Another 2025 study has found a molecular mechanism for the metabolic reprogramming of macrophages, and LT-α promotes aerobic glycolysis and M1 polarisation by activating NF-κB signalling.¹²¹ Macrophages in the degenerative niche are exposed to ECM fragments, DAMPs, lactate, low pH and ROS simultaneously and are thus converted into an inflammatory metabolic state. The resulting macrophages release IL-1β, TNF-α, IL-6, MMPs and other chemokines to increase matrix degradation and disc-cell stress.

Effects of the Loop: ECM Degradation, Cell Death and Pain Sensitisation

At the level of tissue, IL-1β and TNF-α inhibit ECM synthesis, increase MMP and ADAMTS activity, reduce ACAN and COL2A1, and promote matrix disorganisation. Oxidative damage and mitochondrial dysfunction cause all kinds of cell damage, such as senescence, apoptosis, pyroptosis and ferroptosis. Recently, studies have connected ferroptosis-associated chemokine signatures, mitochondrial reprogramming and iron-dependent oxidative injury to IVDD progression.^122,123 Pyroptosis is also a type of damage that links metabolic stress and inflammation. NLRP3 activation promotes maturation of IL-1β and IL-18, gasdermin-mediated membrane injury, and release of additional inflammatory mediators.⁸⁵

Recently, in 2025, some research has shown that glycolysis and pyroptosis work together to promote a vicious cycle in IVDD. Glycolysis promotes NP-cell pyroptosis and IL-1β release via an LDHA-dependent pathway, thus forming a self-amplifying inflammatory loop.¹²⁴ Restoration of mitochondrial quality control can break the cycle. Metabolic reprogramming induced by a mitophagy activator significantly reduces lactate production in senescent NP cells, decreases histone H3 lysine 18 lactylation (H3K18la), suppresses the transcription of the pro-inflammatory gene THBS1, and blocks downstream inflammatory signalling. This study offers direct evidence that mitophagy has an anti-inflammatory effect by regulating the lactate–H3K18la–THBS1 metabolic–epigenetic axis.¹²⁵ As a result of the above changes, the disc has lost most of its matrix-producing cells and has become a degenerative inflammatory lesion with little cell turnover.

Pain-related remodelling can be regarded as a relatively late result of this cycle. Structural damage, inflammatory cytokines, a low pH, and neurotrophic factors all promote nerve and blood-vessel ingrowth in normally aneural areas of the disc. Experimental studies of disc injury have shown that VEGFA coordinates intradiscal vascular and neurite ingrowth and exacerbates chronic low-back-pain-like behaviour.¹²⁶ Endplate inflammation and Modic changes extend the pathological unit beyond the disc to include the disc, endplate and adjacent bone marrow. Concepts from MRI also propose that these structures should be viewed as an integrated degenerative complex rather than as three separate areas.¹²⁷ Lactate-driven acidosis, succinate-related inflammatory amplification and kynurenine-related neuroimmune regulation may thus cooperate with mechanical damage to maintain pain sensitisation.

Bidirectional Regulation: The ACE–PSAP–GPR37 Axis as a Molecular Model for an Immunometabolic Loop

Not all macrophage-disc cell interactions are unidirectional pathogenic amplifications. A 2025 study has identified a bidirectional, mutually reinforcing regulatory loop for disc homeostasis. The ACE-PSAP-GPR37 axis constitutes a full-loop reciprocal circuit where disc cells signal via ACE/PSAP to macrophage GPR37, promote M2 polarisation and TGF-β secretion, and receive feedback to regulate PSAP-Sortilin trafficking in disc cells.⁵⁰ These findings have two important implications. Macrophages and dendritic cells do not have to be abnormal for them to promote the regeneration of damaged tissues. Second, it proposes a molecular model of an immunometabolic loop in which the metabolically regulated signalling molecule PSAP acts via the immune receptor GPR37 to modify macrophage functions, and the macrophage-derived factor TGF-β provides negative feedback to regulate disc-cell metabolism. Another study in 2025 has presented some applications of this idea in therapy. A sequential drug-delivery system first releases angiotensin-(1–7) to improve the inflammatory environment and modulate macrophage phenotype, then releases α-mangostin to regulate ECM metabolism, and thus achieves temporally controlled modulation of macrophage–NP-cell interactions.¹²⁸

Together, these models show that the development of IVDD is cyclical rather than linear. Initiating risk factors disrupt endplate transport and matrix organisation. NP cells are then in a modified glycolytic, mitochondrial and amino acid metabolic state. Chemokines and DAMPs attract macrophages to expand the inflammatory and catabolic response. Disc cells undergo senescence and regulated cell death, lose ECM, develop neurovascularisation, and increase endplate inflammation; thus, pain and structural damage worsen. Evidence from 2025–2026 increasingly shows three main characteristics of this loop: multiple initiating nodes, such as mechanical stress via PIEZO1-Ca²⁺, metabolic stress due to lactate or succinate accumulation, and inflammatory signalling through LT-α-NF-κB, can each start the circuit;^117,121 positive-feedback amplification, such as the senescent NP cell–M1 macrophage–accelerated NP senescence loop;¹²⁰ and metabolic–epigenetic regulation, such as the mitophagy–lactate–H3K18la–THBS1 axis.¹²⁵ The value of this model is not that all the connections have been fully illustrated in IVDD, but that it offers a testable system connecting metabolism, immunity, matrix degeneration and pain. A schematic overview of this proposed metabolite-driven macrophage–disc cell crosstalk is shown in Figure 1.

Figure 1.

Metabolite-driven macrophage–disc cell crosstalk in intervertebral disc degeneration: Degenerative stresses, including impaired nutrient diffusion, endplate calcification, hypoxia, oxidative stress, and inflammation, reprogram nucleus pulposus, annulus fibrosus, and cartilaginous endplate cells. (A) Lactate axis: lactate accumulation promotes acidosis, ASIC1a/ASIC3-mediated Ca2+ influx, mitochondrial stress, NLRP3 activation, and lactylation. (B) Succinate axis: mitochondrial dysfunction may engage the proposed succinate–SUCNR1–HIF-1α–NLRP3 axis and amplify inflammatory signalling. (C) Kynurenine axis: altered tryptophan metabolism through IDO/TDO generates kynurenine and may activate AhR signalling, thereby modulating immune regulation, macrophage function, oxidative stress, and neuroimmune responses in a context-dependent manner. Chemokines, DAMPs, ROS, and ECM fragments recruit and reprogram macrophages, which then release inflammatory cytokines and matrix-degrading enzymes. This feed-forward immunometabolic loop promotes ECM degradation, cellular senescence, regulated cell death, neurovascular ingrowth, and pain sensitisation.

Therapeutic Implications: Targeting Immunometabolic Loops in IVDD

Based on the integrated immunometabolic model presented above, IVDD treatment should not aim to suppress inflammation or promote matrix repair in isolation. It should also be in a metabolic state that regulates macrophage-disc cell communication. Table 2 shows potential immunometabolic intervention targets, their expected effects, possible risks and current stages of development.

Table 2.

Potential Targets for Immunometabolic Intervention in IVDD

Target	Pathway	Expected Effect	Possible Risk	Development Stage	Refs
SUCNR1/GPR91 and succinate signalling	Succinate–SUCNR1–HIF-1α–NLRP3–IL-1β signalling, mainly inferred from inflammatory macrophage biology.	If active in IVDD, SUCNR1 antagonism may reduce succinate-driven macrophage activation, IL-1β secretion, and disc-cell catabolism. Microbiota-derived succinate is also identified as a core metabolite.	Direct IVDD evidence remains limited. SUCNR1 signalling is context-dependent and may be pro-inflammatory or anti-inflammatory depending on macrophage state.	Hypothesis-generating for IVDD. Priorities are to quantify succinate in human discs, map SUCNR1 across NP, AF, CEP cells and macrophage subsets, and test effects on ECM catabolism, inflammation, and pain. The SIRT5-AIFM1 succinylation axis is validated in a rat model.	[73, 78, 82, 89]
SDH/FH-related TCA modulation and mitochondrial quality control	TCA-cycle remodelling, complex II/SDH/FH balance, mitophagy, mitochondrial fusion and fission, ROS control, and inflammasome priming.	Reduce mitochondrial ROS, restore energy homeostasis, limit NLRP3 activation, and indirectly normalize possible succinate accumulation.	Mitochondrial pathways are essential for cell survival; systemic modulation may be toxic and may interfere with physiological HIF adaptation.	Preclinical IVDD evidence for mitochondrial quality control is increasing, whereas succinate-specific intervention remains unvalidated. Melatonin restores mitochondrial homeostasis through PGC-1α, and exogenous mitochondrial transplantation is validated in a rat model.	[80, 129–131]
IDO1/TDO/KMO–AhR modulation	Tryptophan–kynurenine–AhR signalling; regulation of immune tolerance, oxidative stress, macrophage/T-cell function, and neuroimmune signalling.	Potentially modulate chronic inflammation, shift neurotoxic kynurenine metabolites, and provide candidate serum or tissue biomarkers for inflammatory or pain-related phenotypes.	The pathway may be protective or pathogenic depending on timing and metabolite profile; systemic IDO/AhR/KMO modulation has broad immune effects.	Exploratory for IVDD. A 2025 network pharmacology study identifies AhR as a core target in lumbar disc degeneration, and postoperative pain in patients with lumbar disc herniation is associated with quinolinic acid levels.	[97, 105, 132, 133]
Gut microbiota–tryptophan–AhR intervention	Microbiota-derived tryptophan metabolites, kynurenine flux, AhR ligands, and systemic low-grade inflammation.	May indirectly reduce disc inflammation, oxidative stress, and pain susceptibility, and may help define a gut–disc immunometabolic axis.	Causality, responsible metabolites, and patient stratification remain unresolved. Microbiome responses are highly individualized and are not restricted to a specific anatomical site.	Early animal and genetic-epidemiology stage with Mendelian-randomization evidence for causality. A 2025 study provides causal evidence linking gut microbiota, 1,400 circulating metabolites, and IVDD. Animal serum metabolomics also identifies changes in tryptophan-related metabolites, including kynurenine.	[108, 109, 134, 135]
Macrophage metabolic reprogramming	Functional macrophage-state control beyond the M1/M2 classification, including glycolysis, mitochondrial metabolism, efferocytosis, cytokine release, and inflammation-resolution programs.	Reduce IL-1β, TNF-α, IL-6, CCL2, MMPs, and catabolic macrophage–disc cell crosstalk while promoting inflammation resolution and ECM-compatible repair.	Broad macrophage suppression may impair debris clearance, innate defense, and reparative remodelling; overly simple M1/M2 conversion may fail to capture disease-stage complexity.	Strong preclinical rationale. Spatial phenotyping and functional readouts in painful versus non-painful human discs are required. iMSC-derived exosomes reprogram metabolism through miR-100-5p/mTORC1 and break the vicious cycle; an on-demand cooperative delivery system simultaneously suppresses SASP and reprograms macrophages; and a pharmacological review of macrophage reprogramming targets is available.	[14, 43, 120, 136, 137]
EV-, hydrogel-, and nanoparticle-based local delivery	Engineered EVs, macrophage-derived sEVs, dECM hydrogels, and nanocarriers delivering miRNAs, proteins, or anti-inflammatory cargoes.	Improve intradiscal retention, combine immunomodulation with ECM repair, reduce systemic exposure, and enable multi-target therapy.	Batch heterogeneity, cargo instability, immunogenicity, off-target leakage, uncertain dosing, and long-term retention remain major barriers.	Advanced preclinical translational platform. CAP peptide-modified engineered EVs deliver RRAGD to restore lysosomal homeostasis, and a systematic review of engineered EVs for IVDD is available.	[112, 138, 139]
CEP permeability improvement plus metabolite clearance	Restoration of nutrient diffusion and waste/lactate clearance across the cartilage endplate–disc–bone marrow interface.	Improve oxygen and glucose delivery, reduce retention of acidic metabolites, and enhance the efficacy of biologics, EVs, or regenerative cells.	Excessive vascular or neural ingrowth may worsen pain or disrupt disc immune privilege; endplate-targeted interventions are technically challenging.	Conceptual to early preclinical stage. An endplate-targeted engineered exosome combined with an acid-neutralizing hydrogel provides preliminary evidence. MRI-based work also examines the association between endplate injury and lactate metabolism.	[19, 28, 140, 141]

Abbreviations: IVDD, intervertebral disc degeneration; NP, nucleus pulposus; AF, annulus fibrosus; CEP, cartilaginous endplate; ECM, extracellular matrix; MCT, monocarboxylate transporter; ASIC, acid-sensing ion channel; SUCNR1, succinate receptor 1; AhR, aryl hydrocarbon receptor; EV, extracellular vesicle.

The immunometabolic model of IVDD indicates that future treatments should also address pain relief and replacement of lost matrix. Treatments will also need to function in a hostile microenvironment that constantly promotes deterioration. In poorly vascularised areas of the degenerated disc, hypoxia, reduced nutrient diffusion, lactate accumulation, acidosis, mitochondrial dysfunction, increased ROS, inflammatory macrophage infiltration and decreased ECM synthesis often occur simultaneously.^19,142–144 The above reasons are related. Therefore, a more reasonable translational strategy is to address metabolic buffering, immune modulation and matrix repair simultaneously as interrelated issues.

Targeting Lactate Metabolism and Acidic Stress

Now, the lactate axis is one of the more promising metabolic targets for IVDD, and it needs to be regulated properly. NP cells are physiologically hypoxic and rely on glycolysis; therefore, complete inhibition of glycolysis or LDHA activity may injure disc cells rather than protect them.^19,144 Ideally, one should reduce the pathological lactate overload and acid stress while still meeting the basic demand for glycolysis of NP-cells. Therefore, LDHA inhibition may be effective only in the presence of excessive glycolysis, senescence-associated lactate accumulation, or inflammatory metabolic reprogramming. Over time, early-stage NP cells may still need glycolytic flux for survival, but in advanced degeneration, lactate accumulation and a drop in pH are increasingly harmful.

A 2026 study has put forward a new strategy for metabolic correction. The researchers have constructed a biogenic Fe-N-C artificial metabolic enzyme that is a single-atom nanozyme with catalytic performance comparable to natural metabolic enzymes in a hypoxic environment. Spatial dynamic metabolomics shows that this artificial enzyme efficiently converts excess lactate into pyruvate, reduces glutathione, and subsequently regulates the intra- and extracellular microenvironments through coordinated metabolic modifications of the mitochondria and the ECM. Not all LDHA inhibitors have the same effects on glycolysis. It does not produce excess lactate and thus avoids pathological lactate accumulation; it maintains normal glycolytic adaptation.¹⁴⁵

MCT1 and MCT4 are also treatment goals. Transporters regulate lactate transport in the cell and help maintain pH balance. Modulation of MCTs in the disc should not be equated with inhibition of lactate export. Too strong an inhibition of lactate efflux will cause intracellular acidification of NP cells, and if extracellular lactate is not removed, an acidic disc microenvironment will occur. Therefore, next-generation MCT-targeted therapies need to regulate lactate production, export and clearance locally or in a cell-type-selective manner.^19,144

pH-buffering biomaterials are likely more suitable for disc biology than systemic metabolic inhibitors. Injectable hydrogels, ROS/pH dual-responsive hydrogel-nanoparticle systems, and acid-responsive drug-delivery platforms can reduce acidic stress, release anti-inflammatory agents, and provide a matrix-like support for cell survival.^{142,143,146,147} Guo and others designed a lactate-capturing microgel that carried a functionalised miR-155 nanocarrier. Chitosan-coated microgels bind lactate, are pH-responsively dissociated, and release SS31 to regulate mitochondrial metabolism. A three-in-one platform for lactate clearance, miRNA delivery and mitochondrial protection can also be used as a new route for pH-buffering biomaterials.¹⁴⁸ At the same time, Zhan et al have developed CEP-targeted engineered exosomes combined with an acid-neutralizing hydrogel to achieve a dual-therapy effect via endplate-targeted delivery and acid microenvironment neutralisation.¹⁴⁰ Therefore, such materials are highly attractive to IVDD as the disc is poorly vascularised and systemic drugs fail to penetrate effectively. Local delivery can maintain a high therapeutic concentration in the disc and limit systemic exposure. Lactate-scavenging hydrogels or nanomaterials can further reduce local lactate; however, to some extent, the end product of metabolism is still required for life.

Downstream acid-sensing mechanisms are relatively specific therapeutic targets. ASIC1a and ASIC3 convert extracellular acidosis into intracellular Ca²⁺ influx, mitochondrial damage, ROS production and regulated cell death.^57–60 Inhibiting ASIC1a may thus protect NP cells from acid-induced apoptosis, ferroptosis and inflammatory injury. NLRP3 inflammasome inhibition is another way. Acidic stress, ROS and mitochondrial dysfunction activate NLRP3 to promote caspase-1 activation, IL-1β/IL-18 maturation and pyroptosis.¹⁴² Several natural compounds targeting NLRP3 have shown efficacy in IVDD models in 2025. Dihydromyricetin suppresses NLRP3 inflammasome-mediated pyroptosis via the Keap1/NRF2/HO-1 pathway;¹⁴⁹ forsythoside A reduces ECM degradation by inhibiting PI3K/AKT/NF-κB-mediated NLRP3 activation and pyroptosis;¹⁵⁰ and (Z)-ligustilide inhibits NP-cell pyroptosis through the Atg5/NLRP3 axis.¹⁵¹ NLRP3 blockade may thus disrupt the lactate-acidosis-inflammation axis, and pH correction should be employed instead of using it alone as a general anti-inflammatory measure.

Lactylation is a new-generation treatment mode. Research on IVDD in recent years has shown that lactate-derived lysine lactylation regulates AMPKα and other proteins related to autophagy, oxidative defence, cellular senescence and ECM metabolism.^66,68 Not all lactylation events need to be eliminated. Identify the damaged lactylation sites in some cell types, reduce excessive AMPKα lactylation to restore autophagy and matrix homeostasis, and inhibit harmful SOD1 lactylation to protect antioxidant enzyme function. Before applying the above concepts in therapy, adaptive lactylation needs to be differentiated from pathological lactylation.

Targeting the Succinate Axis and Mitochondrial Quality Control

The succinate axis is mechanistically plausible but has not been verified in IVDD. Accumulation of succinate in inflammatory macrophages can stabilise HIF-1α and promote IL-1β expression, and extracellular succinate may signal via SUCNR1/GPR91.^73,78 According to the above model, antagonists of SUCNR1, HIF-1α modulators, SDH/FH-related metabolic regulators and NLRP3 inhibitors can reduce macrophage-driven inflammatory amplification in principle. However, at present, this strategy has not yet been disaggregated. Direct evidence of succinate accumulation in human degenerative discs and evidence that SUCNR1 blockade attenuates IVDD are lacking.

A relatively safe entry point is to strengthen mitochondrial quality control. Mitochondrial dysfunction is repeatedly involved in IVDD, and restoring mitophagy, mitochondrial biogenesis, fusion-fission balance and redox homeostasis may reduce ROS generation, inflammasome activation and cell death.^80,129 Several studies in 2025 have reported significant progress in mitochondria-targeted therapy. Lan and others have shown that melatonin activates PGC-1α signalling, promotes mitochondrial biogenesis, regulates mitochondrial dynamics and mitophagy, maintains mitochondrial homeostasis, and thus reduces excessive apoptosis of NP cells and ECM degradation.¹³⁰ Yang et al used single-cell RNA sequencing data to propose the exogenously introduced mitochondria transplant system for IVDD. Transferred mitochondria improve mitochondrial quality control in NP cells by endocytosis, fusion with endogenous mitochondria, or transfer through tunnelling nanotubes to neighbouring cells. Intradiscal mitochondrial transplantation prolonged puncture-induced IVDD in rats significantly. Recently, some scholars have attached bioactive macromolecules to the outside of mitochondria to achieve antioxidant and anti-inflammatory effects, substantially improving the therapeutic performance.¹³¹ The above modifications may indirectly regulate the TCA cycle, cause an increase in succinate, and thus be attributed to succinate. At present, the succinate–SUCNR1–HIF-1α–NLRP3 axis is best viewed as a testable therapeutic hypothesis. Measure succinate in disc tissue before the start of drug development, map SUCNR1 expression in NP cells, AF cells, CEP cells and macrophage subsets, and determine whether modulation of this axis improves ECM synthesis and pain-related outcomes.

Targeting the Kynurenine Pathway

The kynurenine pathway is not as well-developed in IVDD as the lactate- and succinate-axis systems, but it may still play a role in immune regulation and pain. IDO1, TDO, and KMO regulate tryptophan catabolism into kynurenine and its derivatives. Other inflammatory and neuroimmune disorders have also been studied in terms of IDO1 inhibitors, AhR modulators and KMO inhibitors to modulate immune response, oxidative stress and pain-related signalling.^132,133 In IVDD, the above approaches are still exploratory because the roles of tryptophan-kynurenine metabolism in disc cells and infiltrating immune cells have not been clearly identified. Wang et al have identified AhR as a key target for lumbar disc degeneration and provided genetic and transcriptomic support for AhR-directed strategies;⁹⁷ however, pharmacological intervention studies are still in their initial stages.

Kynurenine signalling in the disc is protective under some circumstances and harmful in others. Kynurenine-AhR signalling can suppress excessive inflammation and promote immune tolerance, but prolonged activation may impair tissue repair, cause immune dysregulation, or alter neuroimmune sensitisation.^132,133 KMO inhibition can reduce the generation of the neurotoxic metabolite quinolinic acid and change the flux of the pathway to kynurenic acid; therefore, it may be associated with discogenic pain or DRG sensitisation. However, this idea has largely been extrapolated from pain and neuroinflammation research and lacks direct IVDD evidence. The first step is to identify potential biomarkers; therefore, we will measure tryptophan, kynurenine, kynurenic acid, quinolinic acid and the kynurenine/tryptophan ratio in the serum, disc tissue and pain-related clinical phenotypes.

Gut microbiota intervention is another potential, but still relatively nascent, research direction. Recently, some studies have found that alterations in the gut microbiome can cause IVDD, and fecal microbiota transplantation has been used experimentally to mitigate it.^134,135 Because gut microbiota regulate systemic tryptophan concentrations and AhR ligands, the gut–tryptophan–AhR–disc axis warrants further investigation. Probiotics, prebiotics and other microbiota-based interventions should not be promoted as established IVDD treatments until a direct connection between microbial tryptophan metabolism, disc inflammation and pain has been confirmed.

Targeting Macrophage Metabolic Reprogramming

Macrophage-centred therapy provides a broader mode of integration for lactate, succinate and kynurenine signalling. We aim to identify and regulate the functions of disease-associated macrophages more precisely, rather than converting M1 macrophages into M2 macrophages. The goal in IVDD is to suppress sustained inflammatory metabolism, enhance efferocytosis, reduce the release of IL-1β, TNF-α and IL-6, and promote repair programs that are compatible with matrix homeostasis.^14,43 The above goals can be achieved by inhibiting excess glycolysis, improving mitochondrial function, reducing the level of ROS, suppressing chemokine-mediated recruitment, and delivering anti-inflammatory nucleic acids or proteins.

Macrophage reprogramming will be employed to address the problem of IVDD in 2025. Hou and others have summarized how the IDD microenvironment modifies the function of macrophages through hypoxia and acidosis; how NF-κB, PI3K-Akt and Nrf2 regulate macrophage polarisation; and how pharmacological or exosome-mediated reprogramming promotes an M2-like phenotype.¹³⁷ Xiang and others have shown that exosomes from human iPSC-derived mesenchymal stem cells (iMSCs) can disrupt the vicious cycle of senescent NP cells, M1 macrophages, and accelerated NP-cell senescence via metabolic reprogramming.¹²⁰ Mechanistically, these exosomes deliver miR-100-5p to inhibit the mTORC1/glycolysis pathway and reprogram M1 macrophages into anti-inflammatory M2 macrophages. iMSC exosomes inhibit the development of IVDD in a mouse model. A contemporary study in ACS Nano reports an on-demand co-delivery system that simultaneously suppresses the SASP of senescent NP cells and reprograms macrophages to remodel both parts of the senescent microenvironment.¹³⁶

Extracellular vesicles, engineered exosomes, nanoparticles and hydrogels are all feasible carriers for these interventions. Engineering strategies for EV therapy advance significantly in 2025. Liao et al built an Fc/TRIM21 platform to develop CAP-peptide-modified engineered EVs that target NP cells and deliver RRAGD for lysosomal homeostasis restoration. Small extracellular vesicles from M2 macrophages can also be added to decellularised ECM hydrogels, and these immunoregulatory vesicles modify the local degenerative microenvironment to delay the progression of IVDD. Engineered EVs can improve targeting, cargo stability and biological efficacy.^112,138,139 Nanomedicine and injectable hydrogel platforms can also deliver anti-inflammatory agents, antioxidants, siRNA, miRNA and matrix-repair molecules directly to the disc.^{143,146,147,152} Local delivery will be chosen instead of systemic immunomodulation to prevent suppression of the body’s defence system and tissue damage caused by broad-spectrum macrophage inhibition.

Combination Therapy: Metabolic Buffering, Immunomodulation and Matrix Regeneration

Single-target therapy will likely not address all aspects of IVDD. Several Strategies combine metabolic buffering, immune modulation and matrix regeneration. Studies from 2025–2026 provide several examples: (1) A triple-function platform of lactate-capturing microspheres, miR-155 and SS31 for lactate clearance, miRNA delivery and mitochondrial protection;¹⁴⁸ (2) CEP-targeted engineered exosomes combined with an acid-neutralizing hydrogel to achieve targeted delivery and microenvironmental neutralization;¹⁴⁰ (3) An on-demand co-delivery system that simultaneously suppresses SASP and reprograms macrophages;¹³⁶ (4) pH-buffering hydrogels in combination with NLRP3 inhibitors to reduce both acidosis and pyroptosis;^142,143 (5) MCT or lactate-flux modulation in conjunction with macrophage reprogramming to limit lactate-driven immune persistence;^{14,19,43,112,144} (6) Anti-inflammatory exosomes or cytokine-modulating nanoparticles embedded in ECM-mimetic hydrogels to reduce inflammation and promote matrix synthesis;^112,138,152 and (7) Strategies that enhance endplate permeability to increase nutrient supply and metabolite clearance, thereby extending the duration of biological therapies.¹⁴¹

Expand the Range of translational endpoints. The following three indices should not be the only focus of future research. Measure the local pH, lactate concentration, mitochondrial function, macrophage phenotype, inflammasome activity, lactylation status, ECM synthesis, endplate transport and pain behaviour. Both metabolic and immune indicators need to be added to the tests to distinguish immunometabolic therapy from other anti-inflammatory or regenerative treatments.

Knowledge Gaps and Future Directions

Immunometabolism offers a way to connect metabolic stress and immune activation with matrix damage in IVDD, but many links are not yet clear. Another problem is what to do with lactate found in a degenerated disc. Lactate may serve as a metabolic end product under conditions of poor clearance, act as a signal molecule for regulating acid-sensing channels, inflammasome activity and macrophage responses, and promote repair-related programmes in specific macrophage states.¹⁴⁴ Therefore, future studies should not view lactate as uniformly harmful but specify the concentration range, cellular source, spatial distribution and disease-stage-specific function.

Lactylation is relatively unexplored. Lactate-derived lysine lactylation can regulate NP-cell senescence, autophagy and oxidative defence, but it has not been determined whether the disease-relevant lactylation events occur mainly in NP cells, AF cells, CEP cells or infiltrating macrophages.⁶⁶ Lactylation has not been identified as a therapeutic target yet, so single-cell and spatially resolved maps of histone and non-histone lactylation are required. Multi-omics Mendelian Randomisation has identified causal links among lactylation-related genes, such as LRP1 and IVDD.⁷¹ It has provided a genetic basis for the causal test of lactylation-directed interventions, but the corresponding cell-type-specific lactylation events have not yet been located.

Succinate is also promising, but its role in IVDD remains insufficiently validated. It is unknown whether succinate accumulates directly in the degenerated human disc or if it is mainly produced by mitochondrial dysfunction in disc cells and inflammatory macrophages.¹⁹ SUCNR1 expression and function are also unknown. It is unknown whether SUCNR1 is expressed in NP cells, AF cells, CEP cells or specific macrophage subsets of the degenerated disc, and whether its signalling is primarily pathogenic, adaptive or context-dependent at different times.¹⁵³ The SIRT5-AIFM1 succinylation axis has been verified in a rat model,⁸² but the succinylation map of human degenerative discs is still lacking.

The kynurenine/AhR axis remains poorly studied in IVDD. Kynurenine metabolism and AhR signalling regulate immune tolerance, oxidative stress response, and chronic inflammatory remodelling in other immune and neuroinflammatory diseases in a tissue- and metabolite-dependent manner.^92,133,154 It has not been determined whether IDO1–kynurenine–AhR signalling in the disc suppresses excessive inflammation, promotes degeneration, or shows a biphasic response with time and location. A 2025 study identified AhR as a key target for lumbar disc degeneration,⁹⁷ but changes in IDO1/TDO expression among different types of IVDD cells and concentrations of kynurenine and its downstream metabolites in degenerated discs have not been systematically quantified.

Research on macrophage heterogeneity in IVDD should also move beyond the M1/M2 division. Macrophage subsets vary in Pfirrmann grades, pain-sensitive and non-painful discs, outer AF fissures, endplate-adjacent regions, and Modic-associated tissues. Although single-cell studies have shown considerable cellular heterogeneity and intercellular communication in human degenerative discs, spatially resolved immunometabolic maps are still lacking.⁴⁶ Liang et al combined spatial transcriptomic sequencing (stRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) in a rat IVDD model to identify potential roles for Pdgfra+ AF cells and Col3hi NP cells in NP fibrosis.¹⁵⁵ This paper offers a direct technical reference for spatial immunometabolic studies in human IVDD tissue. In the future, spatial metabolomics and multiplex immunofluorescence will be combined to pinpoint lactylation-positive areas, CD68+/CD86+/CD206+/SPP1+ macrophage subsets, MCT1/MCT4, SUCNR1, IDO1/AhR, NLRP3, and pain-related nerve fibres within the same tissue structure. Evidence that POSTN is upregulated in severe IVDD and spatially colocalizes with CD68+/CD86+ macrophages has already shown the feasibility of spatial colocalization analysis in human IVDD tissue.¹⁵⁶ A single-cell extracellular-vesicle program scoring method was introduced in 2026 to provide an additional computational tool for mapping immunometabolic reprogramming and immune crosstalk in IVDD.¹⁵⁷

Another unsolved problem is the cause of the change in metabolites and discogenic pain. Increased lactate, altered pH, inflammatory cytokines and neurotrophic factors are all possible reasons, but pain cannot be deduced solely from the extent of degeneration. Human studies directly comparing painful and non-painful degenerative discs are lacking. A 2025 scoping review by Chiu et al has systematically summarized the molecular mechanisms of discogenic low back pain in humans, including pain-related changes in inflammatory mediators, immune-cell infiltration and neurovascular ingrowth, and provided a useful background framework for this research direction.¹⁵⁴ Metabolic therapy also has practical delivery problems because the disc is poorly vascularised, mechanically compressed and matrix-rich. Long-acting, low-toxicity, locally retained delivery systems are thus needed before metabolic modulation can be applied clinically.¹⁵⁸

Future work will pay more attention to spatial immunometabolomics. The first few objectives are to confirm the location of SPP1+ macrophage clusters in human IVDD tissue and determine how closely they are linked to the severity of degeneration, to explore if changes in circulating metabolites, such as lactate, succinate and kynurenine, are causally related to IVDD risk through pQTL-mediated Mendelian Randomization,^47,159 and to build a map of metabolic-cellular organisation across different areas of IVDD pathology, including the central NP, AF fissure borders, CEP regions and Modic areas at the bone marrow interface.¹⁵⁵

Medium-term goals are to: (1) Construct ex vivo disc-slice–macrophage co-culture systems. A disc-tissue slice culture model published in 2025 has shown that cultured disc slices promote macrophage polarisation into a pro-inflammatory type, and the model has provided an experimental platform to study how metabolites regulate macrophage-disc cell interactions;¹⁶⁰ (2) systematically validate molecular markers of the three metabolic axes in human degenerative NP tissue, AF fissure tissue, CEP samples, and Modic-associated specimens;^156,161,162 and (3) conduct comparative metabolomics and immunohistochemistry studies of painful and non-painful discs.¹⁵⁴

The long-term goals are as follows: (1) Explore disulfidptosis, a newly identified type of cell death, and investigate how immunometabolism in IVDD is regulated; determine whether lactate, succinate or other metabolites affect disulfidptosis via the thioredoxin system;¹⁶³ (2) Conduct causal experiments to ascertain whether metabolite-driven cell communication promotes the development of IVDD by means of metabolite supplementation or depletion, specific enzyme inhibitors, receptor antagonists, gene knockdown or knockout, macrophage depletion, macrophage–disc cell co-culture, disc explant culture and rescue experiments;^164,165 and (3) Determine how gut microbiota-derived metabolites, such as succinate and kynurenine, alter the disc microenvironment through the systemic circulation.^89,108

The disc-endplate-bone marrow complex is susceptible to inflammation and changes in bone-marrow signalling; thus, it may be closely related to pain and structural damage.¹²⁷ Validation in human tissue should not be regarded as the end of the research pipeline; instead, it should be added to the beginning of study design. Finally, the two main problems need to be solved: which metabolites are altered in IVDD, and whether these changes in metabolism causally affect macrophage behaviour, ECM metabolism, cell death and pain-related outcomes.

Conclusion

IVDD is accompanied by interacting structural, metabolic and immune disturbances. Within the metabolite-centred framework proposed here, lactate is supported by the strongest IVDD-specific evidence: glycolytic adaptation, impaired clearance and acidosis, MCT-dependent metabolic coupling, ASIC/NLRP3 activation and lactylation link metabolite handling to disc-cell dysfunction. Reported lactate concentrations vary with tissue compartment, experimental model, measurement method and disease stage; values such as approximately 2–5 mM in physiological settings or values above 10 mM in some degenerative models should therefore be interpreted as context-dependent observations rather than universal thresholds. By contrast, direct evidence for the succinate-SUCNR1 and kynurenine-AhR axes in human IVDD remains limited. Succinate-related SIRT5-AIFM1 succinylation has IVDD-specific preclinical support, whereas macrophage SUCNR1 signalling is largely extrapolated from other inflammatory systems. For kynurenine, emerging AhR and tryptophan-pathway observations provide a rationale for study, but a causal kynurenine-AhR macrophage-disc pathway remains unverified.

Taken together, degenerating disc cells may reshape the local metabolic microenvironment and thereby influence macrophage functional states, while macrophage-derived inflammatory and catabolic mediators feed back on disc cells. This proposed self-amplifying immunometabolic loop integrates established findings with testable hypotheses without treating the three metabolite axes as equally validated. Spatial metabolomics in human discs, cell-specific mapping and causal intervention studies are needed to determine which components act as drivers, modifiers or biomarkers of degeneration and pain. If validated, these pathways may provide potential targets for microenvironment-directed therapies.

Funding Statement

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82460940 and 82575116), the Major Project of Gansu Joint Scientific Research Fund (Grant No. 23JRRA1519), the Qihuang Scholar Program of the National Administration of Traditional Chinese Medicine (Grant No. 2025-182), and the Postgraduate Innovation and Entrepreneurship Fund of Gansu University of Chinese Medicine (Grant No. 2026CXCY-020). The funders had no role in the preparation of this review or in the decision to submit the article for publication.

Abbreviations

AF, Annulus fibrosus; AhR, Aryl hydrocarbon receptor; ASIC, Acid-sensing ion channel; CEP, Cartilaginous endplate; DAMPs, Damage-associated molecular patterns; ECM, Extracellular matrix; HIF-1α, Hypoxia-inducible factor 1 alpha; IDO1, Indoleamine 2,3-dioxygenase 1; IL-1β, Interleukin 1 beta; IVDD, Intervertebral disc degeneration; MCT1, Monocarboxylate transporter 1; NF-κB, Nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NP, Nucleus pulposus; ROS, Reactive oxygen species; SUCNR1, Succinate receptor 1; TCA, Tricarboxylic acid cycle; TNF-α, Tumor necrosis factor alpha.

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

Author Contributions

Dong Ma: Conceptualization, Investigation, Data curation, Visualization, Writing – original draft. Jirong Zhao: Conceptualization, Supervision, Project administration, Writing – review and editing. Kaijie Guo: Investigation, Data curation, Writing – review and editing. Wulong Liu: Investigation, Data curation, Writing – review and editing. Hongnian Yin: Investigation, Validation, Writing – review and editing. Yang Zhan: Investigation, Validation, Writing – review and editing. Rui Zhao: Investigation, Visualization, Writing – review and editing. Jing Wang: Investigation, Visualization, Writing – review and editing. Tong Ma: Investigation, Validation, Writing – review and editing. All authors read and approved the final article and agree to be accountable for all aspects of the work.

Disclosure

All authors report Support for the article from Postgraduate Innovation and Entrepreneurship Fund of Gansu University of Chinese Medicine, Qihuang Scholar Program of the National Administration of Traditional Chinese Medicine, Major Project of Gansu Joint Scientific Research Fund, National Natural Science Foundation of China, during the conduct of the study. The authors declare that they have no other competing interests.