Low back pain (LBP) is a common clinical condition that has become increasingly prevalent, with an increasing incidence rate in older age groups. According to statistical reports, the global incidence rate of LBP ranges between 13.1% and 28.5% (Maher et al., 2017). Individuals from lower- and middle-income groups experience LBP less frequently than those in higher-income groups (Hartvigsen et al., 2018; Knezevic et al., 2021). LBP is a leading cause of productivity loss and a major contributor to disability worldwide, placing a significant strain on healthcare systems and global economies worldwide (Luo et al., 2004; Katz, 2006; Freburger et al., 2009).

The intervertebral disc (IVD) is a sealed structure situated between the vertebral bodies of the human spine. It consists of cartilage plates, fibrous rings, and a nucleus pulposus (NP) (Gantenbein et al., 2023). The IVD serves to connect adjacent vertebral bodies and facilitate spinal movement (Nixon, 1986; Stokes and Iatridis, 2004). More than 80% of people aged above 50years experience intervertebral disc degeneration (IDD), which is commonly linked to LBP (Antoniou et al., 1996). Several pathological changes are associated with IDD, such as extracellular matrix (ECM) degradation, inflammation, and cell loss through apoptosis (Sakai and Grad, 2015). Secretion of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6 being the most prominent cytokines) leads to recruitment of host immune cells (macrophages, neutrophils, and T cells) if IVD structural defects are present. As the inflammatory response progresses, immune cells and nociceptive nerve fibers from the dorsal root ganglia begin to infiltrate the damaged IVD tissue. Upon the release of neurotrophic factors by both NP cells and immune cells, the activation of nociceptive nerve fibers occurs, initiating the process of pain transduction. Moreover, the presence of inflammatory cytokines has been found to augment degenerative mechanisms through the activation of ECM breakdown proteins and the inhibition of ECM structural molecule expression (Sun et al., 2022). The causes of IDD are diverse, encompassing genetics; biomechanical changes; alterations in the cellular microenvironment; bacterial or microbial infections; and lifestyle factors such as smoking, alcohol consumption, and obesity. Throughout the IDD process, an increase in pro-inflammatory cytokines within IVD cells is observed, culminating in cell degeneration and necrosis, ultimately leading to ECM degradation (Roughley, 2004; Adams et al., 2009; Kepler et al., 2013; Lin et al., 2023). This, in turn, brings about alterations in the structure and biomechanical properties of the spine. The increased presence of pro-inflammatory cytokines exacerbates the inflammatory response, triggers angiogenesis and neural ingrowth, and prompts the release of pain mediators within the IVD (Figure 1). IDD constitutes a complex and multifactorial process. Inflammation, with or without microbial infection, plays an important role in IDD (Cazzanelli and Wuertz-Kozak, 2020). This inflammation is one of the differentiating factors between symptomatic and asymptomatic IDD, indicating a connection between inflammation and LBP.

In clinical treatment (Chou et al., 2009), doctors assess patients’ symptoms and medical history based on the etiology and pathogenesis of discogenic LBP to determine the appropriate treatment approach. Common treatments include conservative treatment and surgical intervention. Conservative treatment methods are rest, physical therapy, medication, and rehabilitation exercises for pain relief, functional improvement, and promoting recovery. Surgical treatment is often recommended for patients who are nonresponsive to conservative treatment or have severe conditions that may involve procedures such as discectomy, disc replacement, or artificial disc implantation.

Research in basic medical sciences and translational medicine aims to understand the pathogenesis of discogenic LBP and to develop new treatment methods. Studies have examined the structural and histological characteristics of IVDs, along with associated molecular biology and biomechanical changes, using animal models and cell experiments. These investigations help to clarify the mechanisms of IDD and offer a theoretical foundation for new treatment strategies. Research also focuses on the development of novel diagnostic methods and therapeutic approaches. For example, researchers are exploring the use of biomarkers, imaging techniques, and genomics to diagnose discogenic LBP (Bhujel et al., 2022). Technological advancements in fields such as stem cell and gene therapy also show promise for more effective treatment options for patients (Novais et al., 2021).

This review elucidates the underlying inflammatory processes of aseptic and septic inflammation during IDD and introduces various novel drugs, materials, and interventions that can mitigate inflammation, delay the onset and progression of IDD, and alleviate patient pain. We hope that the insights provided in this review will offer new avenues for the clinical treatment of LBP related to IVD infection.

At present, specific blood markers are not implicated in IDD. Clinical identification of IDD relies predominantly on evaluating clinical history, imaging studies, and neurophysiological tests (Wu et al., 2020) (Table 1). Patients often seek medical attention when experiencing persistent lower back and leg pain, signifying the progression of IDD to the middle or late stage. Detecting early IDD poses challenges, as the loss of proteoglycans, Aggrecan, and alterations in certain proteinase levels are not readily discernible microscopically (Knezevic et al., 2021). An innovative quantitative MRI (qMRI) technique has been validated to identify specific characteristic changes associated with IDD at an earlier stage (Russo et al., 2023). In a systematic review conducted by Fabrizio Russo and colleagues (Russo et al., 2023), qMRI technology demonstrated superior efficacy compared to conventional MRI techniques in revealing subtle alterations in water content, proteoglycans, glycosaminoglycans, and select degradation markers, thereby enhancing its capability for the early detection of IDD.

IVD is a natural aging process characterized by a recurring cycle from cell death to matrix remodeling (Kang et al., 2023). Distinguishing the pathological changes between a normally aging intervertebral disc and one affected by degeneration proves challenging (Francisco et al., 2022). Additionally, the pathophysiological alterations in IDD and the radiographic features of various clinically relevant spinal disorders are distinct (Teng et al., 2023). If radiological evidence indicates disc issues, such as disc narrowing or disc protrusion, patients often present with pain as their primary complaint. However, the presence of IDD alone does not always correlate with pain. Despite this, a strong association persists between IDD and LBP (Yang et al., 2022a).

The IVD undergoes numerous physiological and biochemical changes during normal aging or when exposed to factors such as acute trauma, bacterial infection, and gene mutations (Francisco et al., 2022). One of the most notable alterations in intervertebral disc degeneration is the reduction in Aggrecan (proteoglycan) content. Aggrecan, the most abundant proteoglycan in the IVD, experiences diminished levels, leading to the breakdown of the matrix structure (Mohd Isa et al., 2022). Consequently, this results in a reduction in disc height and static water pressure, potentially causing damage to a spinal segment if left unaddressed. Additionally, during the process of intervertebral disc degeneration, there is an increase in the content of fibrous connective proteins, further depleting the levels of Aggrecan. Simultaneously, the levels of enzymes associated with Aggrecan metabolism also undergo changes (Wang et al., 2023).

While collagen content has been observed to increase during the detection of IDD, the proportion of its subtypes undergoes alterations. Type II collagen is the predominant collagen in NP tissue; however, in IDD, the content of cross-linked and denatured type II collagen gradually decreases. Consequently, the ratio of type I collagen to type II collagen rises, leading to reduced fluidity and increased rigidity of the IVD at this stage (Trefilova et al., 2021).

Cell apoptosis is another phenomenon associated with IDD. Unfortunately, apoptosis is an irreversible event that occurs with aging, and reports indicate that, at a specific age, half of the cells in the IVD have already undergone apoptosis (Trout et al., 1982). Research has demonstrated that notochordal cells play a role in the recovery of IDD. In certain animal models of disc injury, the population of notochordal cells persists even as the animals mature (Li et al., 2023a). However, studies have shown that, even in the early stages of human development, there is a significant reduction in viable NP progenitor cells with age. Hence, many researchers believe that the loss of viable NP progenitor cells is a central factor in IDD (Harfe, 2022).

The decline in proteoglycan content constitutes another crucial aspect of IDD. The hydrated matrix tissue is predominantly composed of proteoglycans, and their reduction can impact the comprehensive physiological functions of IVD. This encompasses static water pressure, disc height, biomechanical characteristics, and more, thereby influencing the physiological activities and nutritional metabolism of the vertebral body (Silagi et al., 2018). When proteoglycans are depleted in IVD, the normally elastic fibrous tissue of the disc becomes stiffer, resulting in the generation of unnatural mechanical stress. With the loss of the hydrated matrix, the flexibility and static water pressure of the tissue gradually decrease. The sustained inward pressure on the fibrous ring leads to compression and bulging of the IVD (Peng et al., 2023). Following this, alterations in mechanical stress affect the surrounding fibrous tissue and ligaments, resulting in the thinning of IVD joints and narrowing of the spinal canal. This process persists, leading to IVD rupture and the development of advanced spinal canal stenosis (Kushchayev et al., 2018). Damage to a single spinal segment extends to involve adjacent segments, triggering substantial tissue remodeling in the spine. Additionally, the depletion of hydration in IVD matrix disrupts fluid flow and reduces the capacity to transport essential nutrients, thereby intensifying IDD and hindering regeneration (Yang et al., 2020).

Inflammation is a defensive response of living tissues with a vascular system to damaging factors. It is also a defensive response of the body to stimuli, characterized by redness, swelling, heat, pain, and impaired function. There are many causes of inflammation in body tissues. Inflammation can be categorized into two main groups: infectious inflammation and aseptic inflammation. When the human body is infected by pathogenic microorganisms and bacteria, viruses, protozoa and other infections, and the body produces inflammatory responses such as oozing, necrosis and hyperplasia; this is collectively known as Septic inflammation. If the inflammatory reaction is caused by physical and chemical factors, they are collectively called Aseptic inflammation (Hodges et al., 2021). At the onset of inflammation, whether septic or aseptic inflammation, a large number of inflammatory factors are recruited. Many inflammatory mediators and their associated signaling pathways have critical roles in the onset and progression of IDD (Cazzanelli and Wuertz-Kozak, 2020; Zhao et al., 2021). Pro-inflammatory effects: Inflammatory factors such as TNF-α, IL-1β, and IL-1α (Figures 2, 3) exert pro-inflammatory effects (Li et al., 2023b). These factors stimulate inflammatory responses and cause changes in IVD tissues (Zhang et al., 2021). Their release can lead to pain, vasodilation, and the influx of inflammatory cells (Chen et al., 2022b). Cell apoptosis: Overproduction or excessive accumulation of inflammatory factors may lead to apoptosis (cell death) (Yang et al., 2020; Chen et al., 2022b) or programmed cell death, in IVD cells. This process contributes to degenerative changes and structural damage in IVD tissues, particularly in the NP, during IVD inflammation (Zhao et al., 2021). Cell signaling of cytokines: Inflammatory factors can activate the expression of related genes through cellular signaling pathways, such as the nuclear factor-kappa B (NF-κB) pathway (Zhang et al., 2021). Elevated gene expression can worsen inflammatory reactions and accelerate disease progression (Xia et al., 2019). Induction of neuropathological changes: The release of inflammatory factors can also cause neuropathic changes, including increased pain (Wiet et al., 2017). Research indicates that inflammatory factors such as TNF-α can directly stimulate nerve endings, enhancing pain transmission and leading to neuropathological modifications. Additionally, the presence of certain inflammatory mediators promotes nerve growth into the IVD, increasing susceptibility to LBP (Mohd Isa et al., 2022).

IDD is a pathological degenerative condition affecting the IVD, a connective tissue located between the vertebrae that is essential for spinal kinematics. This degeneration occurs at the tissue, cellular, and molecular levels, resulting in significant alteration of the IVD’s structure and function. This eventually reduces its ability to tolerate compressive loads. Among the various pathological changes in IVD that are associated with IDD, the most common are degradation of the ECM degradation, inflammation, and cell loss through apoptosis (Clouet et al., 2009).

During IVD inflammation, NP cells release increasing amounts of pro-inflammatory cytokines, which can lead to progressive degeneration and the development of pain in the IVD. Among them, TNF-α, IL-1β, IL-6, and IL-17 are particularly prominent. These cytokines are known to facilitate matrix degradation, activate host immune responses, and result in the infiltration of immune cells and nerve fibers. Neural infiltration is particularly noteworthy, as it is a key source of pain in degenerative disc disease (DDD) (Risbud and Shapiro, 2014).

ECM degradation, apoptosis, and inflammation are recognized as the main characteristics of DDD. These processes are interconnected and mutually dependent (Urban and Roberts, 2003). Pro-inflammatory cytokines cause dysregulation of ECM metabolism by upregulating the expression of ECM-degrading enzymes and downregulating the expression of ECM structural components (Wuertz and Haglund, 2013; Risbud and Shapiro, 2014). This internal degradation of the ECM leads to an accumulation of ECM fragments outside the cells, further amplifying the inflammatory response of NP cells (Quero et al., 2013).

Within the realm of pharmaceuticals, small molecules are characterized as substances that possess the ability to bind to certain biological macromolecules, hence exerting influence over distinct biological processes. Small molecules exhibit a maximum molecular weight of 900 Daltons and necessitate efficient diffusion across cellular membranes and the digestive system in order to be absorbed. In general, molecules with a molecular weight exceeding 550 Daltons have greater difficulties in terms of absorption, although certain molecules with a molecular weight of up to 900 Daltons have been observed to effectively traverse the barrier (Hojjat-Farsangi, 2014; Sandborn, 2015). The utilization of small molecules as medicinal agents offers numerous advantages. Due to their diminutive dimensions, they provoke a reduced immunological response within the host and are believed to possess properties that counteract inflammation, apoptosis, and oxidative stress while also exhibiting anabolic and anti-catabolic activities (Kamali et al., 2021). Certain small compounds have demonstrated encouraging outcomes as alternative medicinal agents in laboratory experiments, animal models, and clinical trials (Molinos et al., 2015; Pan et al., 2018). These therapeutic compounds demonstrate a range of phenomena that promote IVD regeneration and hinder degeneration. These include antioxidant, anti-inflammatory, anti-aging, anti-apoptotic, anti-catabolic, and anabolic actions.

Various small molecule drugs, such as naringin, cannabidiol (CBD), epigallocatechin gallate (EGCG), curcumin, icariin, resveratrol, berberine, and tofacitinib, were found to have an impact on the down-regulation of IL-1 and TNF-α in IVD cells, as observed in multiple in vitro investigations. Previous studies have reported that icariin, resveratrol, and EGCG possess inhibitory effects on NF-kB and p38/MAPK signaling pathways. As a result, these compounds are able to regulate inflammatory responses and impede the progression of degenerative cascades (Cao et al., 2016; Xu et al., 2018). Gefitinib, kaempferol, and berberine are further small compounds that selectively inhibit the NF-kB signaling pathway (Zhu et al., 2017; Pan et al., 2018; Lu et al., 2019). In contrast, rhein and uridine In vitro, the intracellular p38/MAPK signaling pathway was observed to be obstructed (Li et al., 2011; Liu et al., 2018).

The examination of anti-inflammatory medicines has demonstrated their efficacy in alleviating symptoms in individuals with IDD. Nevertheless, the precise mechanisms behind their potential anti-inflammatory and rejuvenating activities remain inadequately elucidated. In a study conducted by Li Z et al., the authors discovered the potential of etanercept and tofacitinib in preserving disc homeostasis within intervertebral disc bioreactors using preclinical disc organ culture models. This approach enabled the application of dynamic loading and facilitated nutrition exchange (Li et al., 2020). Etanercept was administered via intradiscal injection while simultaneously replenishing tofacitinib in the culture medium. The study employed immunohistochemistry as a method to evaluate the protein expression levels of IL-1β, IL-6, IL-8, and collagen II in IVD tissues. The expression of IL-1β, IL-6, IL-8, matrix metalloproteinase-1 (MMP1), and matrix metalloproteinase-3 (MMP3) in NP tissue, as well as IL-1β, MMP3, cyclooxygenase-2 (COX-2), and nerve growth factor (NGF) in annulus fibrosus (AF) tissue, was downregulated by the administration of etanercept and tofacitinib. Etanercept and tofacitinib have shown the capacity to counteract the proinflammatory and catabolic milieu in organ culture models of IDD.

IL-1β serves as the primary inflammatory component responsible for expediting the process of disc degeneration. Furthermore, there is an observed elevation in the levels of IL-1β within degenerated discs. In recent studies, it has been observed that luteolin, which belongs to the class of flavonoid glycosides, exhibits anti-inflammatory characteristics. Luteolin exhibited the ability to preserve cellular shape and suppress apoptosis in intervertebral disc NP cells treated with IL-1β. This was evidenced by a decrease in the production of cleaved caspase3 (Lin et al., 2019). Additionally, it demonstrated inhibitory effects on many inflammatory mediators, including nitric oxide (NO), prostaglandin E2 (PGE2), TNF-α, interleukin 6 (IL-6), COX-2, and inducible nitric oxide synthase (iNOS) in NP cells treated with IL-1β. The findings from mechanistic investigations demonstrated that luteolin exerted inhibitory effects on the NF-κB signaling pathway. Furthermore, it was shown that the regulation of luteolin in NF-κB signaling entailed the participation of Nrf2, as seen by the diminished inhibitory effect of luteolin on NF-κB signaling upon Nrf2 knockdown. This finding provides evidence that luteolin has the ability to stimulate the Nrf2/HO-1 signaling pathway, suggesting its potential as a therapeutic intervention for IDD.

Nonsteroidal anti-inflammatory medications (NSAIDs) are commonly employed as the primary therapeutic approach for alleviating pain symptoms by mitigating the inflammatory element of the pain pathway. COX-2 inhibitors belong to a category of NSAIDs that selectively inhibit the enzyme COX-2, resulting in the alleviation of inflammation and pain while minimizing gastrointestinal side effects compared to nonselective NSAIDs. NSAIDs have the potential to be utilized in conjunction with additional analgesics, including paracetamol and mild opioids (such as tramadol), in order to effectively address pain pathways at various stages. Tellegen AR et al. investigated the controlled release and biological effectiveness of celecoxib, a selective COX-2 inhibitor, from polyester amide microspheres in an in vitro setting (Tellegen et al., 2018). The experiment demonstrated that the release of celecoxib in vitro was prolonged for a period exceeding 28 days. This sustained release led to a notable reduction in inflammation, as indicated by the decreased production of PGE2. Additionally, the experiment revealed anti-catabolic effects in NP cells obtained from degenerative IVD, as evidenced by quantitative polymerase chain reaction (qPCR) analysis. Moreover, there is evidence suggesting that inflammation is involved, as indicated by the reduction in tissue levels of PGE2 and the decrease in immunopositivity of neural growth factor. These findings indirectly support the notion that the topical application of COX-2 inhibitors might effectively alleviate pain associated with intervertebral disc degeneration.

Rapamycin is a lipophilic antibiotic mainly used to prevent immune rejection after organ transplantation, owing to its immunosuppressive properties (Webster et al., 2006). It specifically inhibits the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that is crucial for cell growth and proliferation (Mossmann et al., 2018). Rapamycin is a specific inhibitor of mTOR and can also activate cellular autophagy, thereby protecting cells or tissues from further damage (Benjamin et al., 2011). Zuo Rui et al. constructed a mouse model with a degenerated cartilage endplate (CEP). Under the induction of rapamycin-induced autophagy, chondrocyte-like cells in CEP stem cells were protected from TNF-α-induced oxidative stress. The study also showed that rapamycin enhanced the Nrf2/Keap1 pathway, boosting the expression of antioxidant proteins (Zuo et al., 2019). Jinyu Bai et al. designed a reactive oxygen species (ROS)–clearing scaffold loaded with rapamycin (Rapa@Gel). After establishing a rat IVD injury model, Rapa@Gel treatment reduced the proportion of M1-like macrophages and alleviated inflammation in the damaged IVD tissue in rats, showcasing the IVD regenerative potential of rapamycin (Bai et al., 2020). Gao C. et al. (2018) reported that borrelidin treatment induced senescence in rabbit annulus fibrosus stem cells (AFSCs), but after rapamycin treatment, the gene expression of MMP-3, IL-1β, and TNF-α was downregulated in AFSCs. Furthermore, rapamycin could inhibit the multidirectional differentiation potential of AFSCs in a concentration-dependent manner, thus delaying IDD onset (Takahashi et al., 1999).

To date, numerous small-molecule drugs, including growth factors or cytokine inhibitors, have shown compelling and specific therapeutic effects in basic research (Wang et al., 2021; Wu et al., 2022; Chen et al., 2023b). However, none of these small-molecule drugs has yet been successfully applied in clinical settings to ameliorate IDD. There is also a lack of clinical studies on small molecule drugs for the treatment of IDD. Regarding this, the author has summarized the following reasons:

Hence, additional research is essential in identifying crucial targets, refining drug delivery systems, and conducting clinical trials. This necessitates collaborative efforts from experts within the industry.

Sirtuins are a family of protein deacetylases that are highly conserved and depend on nicotinamide adenine dinucleotide (NAD+) for their deacetylase activity. These proteins are pivotal in extending lifespan and delaying the onset of aging-related diseases (Wątroba et al., 2017). They are involved in various metabolic processes, including the regulation of inflammation (Mendes et al., 2017). Notably, several studies have identified the role of specific sirtuins—namely SIRT1, SIRT2, SIRT3, and SIRT6—in the occurrence and progression of IDD and the aging process of IVD cells (Cai et al., 2020; Ma et al., 2022; Hou et al., 2023). These sirtuins influence inflammation, oxidative stress, and mitochondrial dysfunction (Zhang et al., 2020) (Figure 4).

Among the sirtuin family members, SIRT1 is the most extensively studied protein and is associated with aging, cancer, and various degenerative diseases (Yang et al., 2022b). Existing studies indicate that SIRT1 has the potential to reduce inflammation, inhibit oxidative stress, and enhance mitochondrial function. These abilities make it a promising candidate for delaying the onset and progression of IDD (Ji et al., 2018). SIRT1 expression has been detected in NP cells. As IDD progresses, the expression level of SIRT1 mRNA has shown a notable decrease. Furthermore, in vitro tests have shown that activating SIRT1 with resveratrol, a known SIRT1 agonist, promotes NP cell proliferation while inhibiting apoptosis (Wuertz et al., 2011). Yi et al. (Yi et al., 2019) reported that NF-κB knockdown using P65-siRNA significantly reduces LPS-induced NP cell apoptosis and the expression of the pro-inflammatory factors TNF-α and IL-1β. The NF-κB signaling pathway is a crucial mediator in the inflammatory response of IDD. SIRT1 in IDD inhibits the NF-κB pathway and, consequently, reduces IL-1β-induced inflammation, thereby reducing NP cell apoptosis and ECM degradation. Further adding to SIRT1’s capabilities, Hao et al. (Hao et al., 2022) reported that the protein p300 could upregulate the expression levels of FOXO3 by binding to the promoter region of sirt1. This interrupts the Wnt/β-catenin pathway, contributing to reduced inflammation and delayed IDD progression. In addition to regulating the inflammatory response, oxidative stress resulting from excessive production of ROS can accelerate IDD through the modulation of signaling pathways such as NF-κB, MAPK, and PI3K/Akt pathways (Davalli et al., 2016). St-Pierre et al. reported that SIRT1 can inhibit this oxidative stress by inducing the deacetylation of PGC-1α, which leads to the overexpression of antioxidant enzymes, including manganese superoxide dismutase (Mn-SOD), which inhibits oxidative stress. Furthermore, SIRT1 deacetylates FOXO3a and translocates it to the nucleus, leading to upregulated expression of other antioxidant enzymes and peroxidases, protecting cells from damage caused by oxidative stress. During IDD progression, both the number and function of mitochondria in aging NP and annulus fibrosus cells tend to diminish, compromising their cellular function. Miyazaki et al. (Miyazaki et al., 2015) revealed that the administration of recombinant human SIRT1 (rhSIRT1) increased autophagy and reduced nutrient deprivation–induced mitochondrial apoptosis in cultured human NP cells. This suggests that rhSIRT1 might be an effective therapeutic approach for treating IVD-related diseases. In summary, SIRT1 presents a compelling case as a potential clinical target for delaying IDD and providing effective treatment for LBP.

Like SIRT1, SIRT2 is also ubiquitously found in the cytoplasm and nucleus across a variety of human tissues. Although it does not have as specific a regulatory role as SIRT1 in cellular functions, SIRT2 is closely linked to inflammation, oxidative stress response, and mitochondrial function. SIRT2 becomes upregulated under conditions of oxidative stress, leading to the deacetylation of FOXO3a and an increase in the expression of its target genes (p27 kip 1, MnSOD, and Bim). This chain of events subsequently reduces the production of reactive oxygen species (ROS) (Wang et al., 2019b). PGC-1α, a downstream molecule of SIRT2, acts as a transcriptional coactivator for numerous genes and plays a pivotal role in mitochondrial biogenesis, energy management, and cellular survival. It is also instrumental in clearing mitochondrial proteins of ROS (Halling and Pilegaard, 2020). Recent research has revealed that SIRT2 offers protection to annulus fibrosus cells from oxidative stress-induced apoptosis by regulating PGC-1α and inhibiting mitochondrial autophagy (Xu et al., 2019). A study by Yang et al. (Yang et al., 2019) showed that SIRT2 expression is markedly reduced in tissues affected by severe IDD. However, overexpressing SIRT2 in these degenerative NP cells notably inhibits the p53/p21 pathway, thereby slowing down tissue aging. Additionally, SIRT2 overexpression leads to an increase in the production of antioxidant enzymes SOD 1/2, mitigating oxidative stress in IVD cells. Given these findings, SIRT2 holds promise as a future target for preventing and delaying IDD.

In the realm of sirtuins research, SIRT3 stands out as the only member proven to extend human lifespan. Located primarily in the mitochondria, SIRT3 assumes a prominent role in mitochondrial function (Gao J. et al., 2018). Under stressful conditions, mitochondria may overexpress SIRT3, which then boosts the expression of the FOXO3a gene, essential for producing SOD2 and catalase. Advanced glycation end products (AGEs), which are associated with late stages of IDD, are known to induce oxidative stress and impair mitochondrial function (Liao et al., 2019). A study by Song et al. (Song et al., 2018) demonstrated that diminished SIRT3 functionality and reduced mitochondrial antioxidant capabilities are key factors in AGE-induced oxidative stress and the resulting apoptosis in human NP cells. Furthermore, nicotinamide mononucleotide has been shown to enhance SIRT3 functionality and thereby reduce apoptosis in NP cells through the AMPK-PGC-1α pathway (Martin et al., 2017). This suggests that SIRT3 plays a crucial role in preventing AGE-induced apoptosis in human NP cells and may be effective in delaying the progression of IDD by improving mitochondrial redox homeostasis.

Sirt6 has unique enzymatic activities, including both ADP-ribosyltransferase and NAD+-dependent deacetylase functions (Liu et al., 2021). Chen et al. (Chen et al., 2018) showed that levels of Sirt6 tend to decline in the NP cells of older individuals, while its overexpression can deter apoptosis in these cells. Another study by Jiang Hua et al. (Jiang et al., 2021) identified a significant upsurge in the levels of miR-338-3p in NP cells from patients with IDD. Injecting antagomir-338-3p attenuated the inhibitory effect of SIRT6, thus reducing cellular aging and apoptosis in NP cells. In summary, these findings suggest that SIRT6 could be a therapeutic target for delaying IDD progression by mitigating apoptosis in NP cells.

During IVD, there is a steady decline in the population of healthy resident cells, which is accompanied by the progression of catabolic activity while tissue anabolism occurs (Vadalà et al., 2019). In order to promote the natural regenerative processes of degenerative IVD, stem cells can be obtained from diverse origins and afterward transplanted into afflicted host tissues. The concept of “stemness” is a subject of great interest, encompassing the transplantation of transdifferentiated somatic cells, induced pluripotent stem cells, and embryonic stem cells. Undifferentiated stem cells possess the capacity for self-renewal and proliferation, leading to the generation of specialized cells that replenish the population of cells within distinct tissues (Clouet et al., 2019). In this context, it is plausible that these entities possess the capability to release growth factors and cytokines, which serve the purpose of facilitating the functioning of existing cells and enticing or activating nearby progenitor cells. (Clouet et al., 2019; Vadalà et al., 2019). It has been proven that stem cells have been isolated from many tissues, including IVD (Kraus and Lufkin, 2017; Kraus et al., 2017).

Various types of candidate cells have been identified in the field of cell-based IVD therapy. These include NC cells, chondrocytes, MSCs, and NP cells. Some of these cell types have undergone preclinical and clinical investigations (Lufkin et al., 2022). Selection of cell types requires knowledge of disc development as well as understanding of maturation and degeneration-induced cellular changes (Pattappa et al., 2012; van den Akker et al., 2016; Binch et al., 2021). Promising approaches in the field of endogenous repair involve the activation of IVD repair cells, together with the administration of basic biological components such as microRNAs (miRNAs) (Henry et al., 2018; Clouet et al., 2019). Dong et al. (Dong et al., 2019)investigated the role of miR-640 in DDD and inflammation. Having confirmed that miR-640 was upregulated in both DDD tissues and cells, they found that this upregulation could be caused by an inflammatory environment. The application of TNF-α and IL-1β to cells led to a notable augmentation in miR-640 expression, which was facilitated through the NF-κB signaling pathway. In this inquiry, they aim to forecast the potential targets of miR-640 and substantiate the claim that one of its targets is the low-density lipoprotein receptor-related protein 1 (LRP1), which acts as an indirect inhibitor of NF-κB. Combining cell therapies with miRNAs has the potential to have a multiplier impact.

While cell therapy has demonstrated certain functional improvements in basic research when compared to control groups, its clinical translation has produced few satisfactory results. This is attributed to the intricate biological microenvironment of intervertebral discs, the complex mechanical stress on the spine, and the absence of a unified cell treatment strategy. Notable drawbacks include issues such as cell injection leakage, insufficient cell survival time, and ectopic ossification (DiStefano et al., 2022). Additionally, the regulatory measures and ethical concerns associated with cell therapy products derived from human sources pose significant challenges, consuming a substantial amount of time. Numerous studies have suggested that cell therapy achieves therapeutic effects by activating pathways through paracrine signaling molecules (Duan et al., 2023; Zhou et al., 2023). Consequently, extracellular vesicles (EVs) have emerged as a new focal point of research.

EVs can be generated by nearly all cell types. These vesicles encapsulate various types of nanoscale particles, including lipids, nucleic acids, amino acids and their metabolites, diverse proteins, mRNA, short-chain non-coding RNA, and DNA (van Niel et al., 2022) (Figure 5). Exosomes, a subtype of EVs, play a significant role in intercellular communication. EVs act as a crucial means of conveying specific molecules efficiently from source cells to target cells (Buzas, 2023). The phospholipid bilayer on their surface exhibits recognition specificity, making EVs well-suited for precise biological marking and the transport of certain drugs (Jeppesen et al., 2023). EVs represent an emerging field of research in skeletal repair, with the majority of published studies emerging within the last five years (Yin et al., 2022; Ebata et al., 2023; Liu et al., 2023c). Documentation of the efficacy of EVs in various organs and systems exists, and in osteoarthritis (OA), it has been observed that EVs derived from mesenchymal stem cells (MSCs) can inhibit inflammation, downregulate the levels of IL-1β, IL-6, and IL-8, and increase extracellular matrix synthesis, effectively alleviating pain (Li et al., 2022). Although the mechanisms underlying OA and IDD are not entirely identical, evidence suggests that EVs could constitute a promising research direction for treating IDD (Liao et al., 2021).

In a study conducted by Hongxing Hu and colleagues (Hu et al., 2023), Evs derived from pre-treated MSCs under low oxygen conditions were injected into intervertebral disc tissues. The results demonstrated an enhancement in NP proliferation and increased production of proteoglycans and type I collagen. In vivo experiments further elucidated that Evs promote IVD regeneration through the transmission of miRNA-7-5p. In the research led by Zhiwei Liao and collaborators (Liao et al., 2019), it was observed that EVs derived from bone marrow mesenchymal stem cells (MSC-exos) can activate the AKT and ERK pathways, mitigating endoplasmic reticulum (ER) stress-induced cell apoptosis. Additionally, Hongyuan Xing (Xing et al., 2021) and his team integrated the extracellular matrix of thermosensitive cells into a hydrogel, combining it with EVs from adipose-derived mesenchymal stem cells (ADSC) (dECM@exo). This innovative approach, harnessing the biomechanical advantages of a hydrogel, consistently releases vesicles carrying nanoparticles that modulate matrix metalloproteinases (MMPs). This process aims to promote matrix synthesis, reduce degradation, and inhibit inflammation. Animal experiments validated its efficacy in maintaining the homeostasis of the early IVD microenvironment and improving the process of IDD.

While most in vitro experiments in existing studies have demonstrated the benefits of EVs for NP cells and IVD regeneration (Dai et al., 2023; Liu et al., 2023a), few studies have reported their efficacy on annulus fibrosus (AF) cells and cartilaginous endplate (CEP) cells (Yang et al., 2023). Future research could further enhance investigations into these two cell types. Additionally, there is a need to explore efficient methods for cultivating stem cells and Evs molecular carriers, among other considerations (Wu and Sun, 2021). In conclusion, Evs, as an emerging research focus, present unique advantages compared to traditional cell therapies. It is a subject worthy of deeper exploration and holds promise as a novel pathway in clinical treatment.

At present, recent research on the treatment of IDD primarily centers on diverse modalities involving cells, growth factors, small molecule drugs, and combinations with or without biomaterials. Numerous in vitro and preclinical studies have demonstrated the ability of these approaches to induce the regeneration of NP cells through various mechanisms, thereby facilitating the self-repair of IVD. Preliminary results from some clinical trials are also available. The clinical trials focusing on IDD degeneration treatment conducted in the past five years total 12, as summarized in Table 4.