The etiology of LSS is categorized into primary and secondary causes. Primary LSS stems from congenital abnormalities or developmental disorders, while secondary LSS primarily arises from degenerative changes. These changes include decreased intervertebral disc height, facet joint hypertrophy, LF thickening, and spondylolisthesis (1, 3). LSS impacts several anatomical regions: the central canal, lateral recess, and intervertebral foramen. Central canal stenosis results from reduced disc height, disc bulging, facet joint hypertrophy, and LF thickening. LSS is characterized by its dynamic nature; the spinal canal’s space fluctuates with different postures—decreasing during weight-bearing and extension, and increasing during flexion and axial traction. These dynamic changes significantly influence the clinical presentation of LSS symptoms (1). Additionally, LSS can induce nerve root compression, leading to impaired blood flow, occlusion of small arteries, neural ischemia, and diminished nutrient supply to the nerve roots, clinically manifesting as pain, numbness, and weakness (13). Furthermore, stenosis can obstruct venous return, elevate venous pressure, and cause the accumulation of toxic metabolites, which further exacerbates nerve root damage (3).

Inflammatory responses in joints and the LF, particularly the elevation of inflammatory cytokines, are closely linked to the development of LSS. The inflammatory process in LSS is primarily associated with pathological changes of the LF. Studies have demonstrated a strong correlation between LF thickening and the accumulation of scar tissue induced by inflammation. In thickened LF, fibrosis (scar formation) is prominent, with inflammation serving as the catalyst for this process. The thickening of the LF could result from tissue damage caused by mechanical stress, which triggers inflammatory responses and the subsequent accumulation of scar tissue. Research has shown that, in patients with LSS, the LF undergoes fibrosis and loss of elastic fibers, which are associated with the activation of inflammatory cytokines. Within the inflammatory milieu, cytokine release stimulates surrounding cells to synthesize fibrous matrix components, thereby initiating a process of fibrosis that culminates in increased LF stiffness (14). Various inflammation-related cytokines are expressed in the LF, including cyclooxygenase-2 (COX-2), TNF-α, and several interleukins such as interleukin-1 (IL-1), IL-6, interleukin-8 (IL-8), and interleukin-15 (IL-15). COX-2, an enzyme linked to inflammation, has been detected in thickened LF, underscoring the critical role inflammation plays in LF thickening. Cytokines such as IL-1β promote the production of matrix metalloproteinases (MMPs), leading to excessive degradation and remodeling of the ECM, thus accelerating LF thickening (15). MMPs, a class of enzymes involved in ECM degradation, when abnormally expressed, can disrupt tissue structural balance. A recent clinical study (16) on human LF tissue confirmed that IL-6 acts as a critical upstream signal driving MMP-mediated elastic fiber degradation. The research demonstrated that both IL-6 and MMP-2 were significantly upregulated in hypertrophied LF from patients with LSCS, and their levels exhibited a strong positive correlation. Mechanistically, IL-6 directly induces the expression, secretion, and activation of MMP-2 in LF fibroblasts by activating the signal transducer and activator of transcription 3 (STAT3) pathway. Functional assays confirmed that this process ultimately accelerates elastolysis, thereby disrupting the normal elastic fiber architecture of the LF and contributing to its pathological thickening characterized by elastic fiber loss and collagen disorganization. Studies have indicated that chronic inflammation is a significant factor contributing to LF degeneration and thickening in LSS (15–19). Chronic inflammation contributes to LF thickening not only by facilitating ECM degradation but also by directly driving pathological fibrotic deposition. Inflammatory mediators such as IL-6 and TNF-at originating from adjacent degenerative discs, can directly stimulate LF cells to initiate a profibrotic response. Park et al. (20) demonstrated that this response involves a significant upregulation of collagen types I, V, and XI mRNA, promoting aberrant ECM accumulation. Importantly, a recent study employing a novel rabbit model (21) delineated that this inflammatory cascade is initiated by mechanical stress. The stress-induced microenvironment, characterized by M1 macrophage infiltration and the release of pro-inflammatory factors (TNF-α, IL-6), markedly enhances the secretion of transforming growth factor-beta 1 (TGF-β1) from LF fibroblasts. TGF-β1, in turn, acts as a key driver for the transition of fibroblasts into α-smooth muscle actin (α-SMA)-expressing myofibroblasts, culminating in excessive synthesis of collagens (e.g., types I and III), aberrant ECM deposition, and ultimately, fibrotic hypertrophy of the LF.

Notably, while IL-6 has been identified as a key mediator in this inflammatory-fibrotic cascade, the upstream regulatory mechanisms that control IL-6 expression in hypertrophic LF remain an important area of exploration. Recent research (19) has uncovered a critical role of angiopoietin-like protein 2 (Angptl2) in this process—one that links inflammation, angiogenesis, and LF thickening by modulating IL-6 signaling. These investigations further indicate that Angptl2, which regulates inflammation and angiogenesis, is highly expressed in hypertrophic LF. Angptl2 promotes inflammatory responses by activating IL-6 expression. The expression of IL-6 is significantly elevated in hypertrophic LF tissue and positively correlates with LF thickness and Angptl2 levels. Angptl2 binds to integrin α5β1, a cell surface receptor involved in ECM signaling on LF fibroblasts, activating the NF-κB signaling pathway. This activation induces the expression and secretion of IL-6. These findings highlight the intimate relationship between inflammation and LF degeneration and thickening, underscoring the critical role of inflammatory responses in the pathological mechanisms of LSS.

The release of inflammatory mediators not only worsens tissue degeneration but also heightens pain sensitivity by affecting nerve roots. Research indicates that the buildup of macrophages is linked with the release of inflammatory cytokines, which promote inflammation and edema of the nerve roots, thus intensifying pain. Therefore, the release of inflammatory mediators plays a crucial role in the pathological processes following spinal cord injury (22). Inflammation also contributes to the formation of localized edema in neural structures, further narrowing the spinal canal and nerve root pathways, thereby worsening nerve compression symptoms. This results in clinical manifestations such as lower back pain, radicular pain, and cauda equina syndrome (15). Consequently, controlling the inflammatory response is vital for alleviating symptoms associated with LF thickening and for decelerating disease progression.

LSS is often associated with intervertebral disc degeneration, LF thickening, and other structural changes in the spine, which incite localized inflammatory responses. Research has demonstrated that the irregular expression of inflammatory factors plays a crucial role in the onset, progression, and prognosis of LSS. Modulating these inflammatory responses by decreasing the release of pro-inflammatory factors and fostering the production of anti-inflammatory factors can effectively prevent or control the advancement of LSS (27). Inflammatory factors and immune cells are pivotal in the pathological processes of LSS. Damaged areas attract immune cells like macrophages, which manage local inflammatory responses by secreting mediators such as cytokines and chemokines. In the development of LF thickening, inflammatory factors are key drivers. LF injury triggers an early inflammatory response, significantly increasing pro-inflammatory factors like IL-6. As inflammation persists, macrophages invade the damaged tissue, and pro-inflammatory factors intensify the inflammatory reaction, leading to fibrosis, structural changes, reduced elasticity, increased stiffness, and LF thickening. This fibrosis further exacerbates spinal canal stenosis and contributes to related clinical symptoms (28). Conversely, anti-inflammatory factors like IL-10 can mitigate inflammatory responses and promote tissue repair, thereby alleviating LF fibrosis and thickening (19). This mechanism highlights the central role of the inflammatory state in LF’s pathological changes, suggesting that factors regulating inflammatory responses may serve as potential therapeutic targets for LSS. Macrophages are critical in the recovery process following spinal cord injury and are key effector cells in response to spinal injury. Under inflammatory conditions, macrophages often polarize toward the M1 phenotype, releasing pro-inflammatory factors such as TNF-α, IL-6, and interferon-γ (IFN-γ), which contribute to chronic low-grade inflammation and delay tissue repair. In contrast, M2 macrophages secrete anti-inflammatory factors like interleukin-4 (IL-4) and IL-10, which help suppress inflammation and promote tissue repair. EA therapy has been shown to influence macrophage polarization by inhibiting the pro-inflammatory effects of M1 macrophages and promoting their polarization toward the M2 phenotype, thus alleviating inflammation and accelerating tissue repair (14, 29). Mingyang Yan et al. (30) and colleagues validated this mechanism using a rat model of skeletal muscle contusion-induced fibrosis. Their study showed that EA significantly reduced M1 macrophages and their markers, such as IFN-γ, while increasing M2 macrophages and their markers, such as IL-4 and interleukin-13 (IL-13). These findings suggest that EA effectively modulates inflammatory responses and supports the repair and regeneration of injured skeletal muscle by facilitating macrophage polarization. Moreover, EA alleviates fibrosis and enhances the regeneration of muscle fibers. Based on these findings, EA may hold therapeutic potential for LSS, particularly in the pathology of LF thickening, which is closely linked to fibrosis. By modulating macrophage polarization, EA could inhibit fibrotic responses and improve the pathological changes caused by LF thickening, offering a novel approach to treating LSS. Through phagocytosis and the secretion of degradative enzymes, macrophages can help clear damaged tissue, aiding in restoring functionality in the affected area (22, 27, 31). While the inflammatory response contributes to tissue repair, it may also exacerbate pain. Inflammatory mediators can stimulate nerve fibers, leading to a reduced pain threshold and spontaneous pain occurrence (10, 31). Thus, inflammation in LSS patients may not only be part of the pathological process but also a direct cause of symptom variation (see Figure 2 )

EA has demonstrated considerable effectiveness in treating inflammation (31–34), particularly in alleviating pain associated with inflammatory processes. Its analgesic effects are primarily achieved through the modulation of various inflammatory factors. EA mitigates inflammatory responses by activating bioactive substances within the body and inhibiting the release of pro-inflammatory cytokines. This process involves EA’s regulation of immune cells, which promotes the expression of anti-inflammatory factors, thus improving pain and inflammatory conditions (23). Specifically, EA reduces levels of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, while enhancing the expression of anti-inflammatory cytokines like IL-10. This regulatory effect is primarily mediated through its influence on immune cells, including macrophages and regulatory T cells (10, 29, 35) (see Figure 3 ). Additionally, EA can activate the hypothalamic-pituitary-adrenal (HPA) axis, encouraging the secretion of cortisol from the adrenal glands to suppress inflammatory responses. The HPA axis is a crucial regulatory system for the body’s response to stress and inflammation. When the body encounters pain or inflammatory stimuli, the HPA axis is activated, causing the hypothalamus to release adrenocorticotropic hormone (ACTH), which subsequently stimulates the adrenal glands to secrete cortisol. As a key anti-inflammatory hormone, cortisol effectively suppresses inflammation and aids in restoring homeostasis (33).

Studies indicate that EA can relieve pain caused by LSS through various mechanisms, including inducing neurogenic inflammation, releasing endogenous substances, and activating anti-inflammatory cascades. These processes ultimately lead to the release of endogenous opioids (36). Furthermore, in an animal study, EA stimulation at the Zusanli (ST36) acupoint was found to reduce paw swelling caused by delayed-type hypersensitivity (DTH), inhibit inflammatory cell infiltration, and lower the levels of specific immunoglobulins IgG and IgE. EA also helps regulate the Th1/Th2 balance by reducing the production of Th1-type cytokines, such as IFN-γ and TNF-α. Th1 cells are responsible for pro-inflammatory responses, while Th2 cells are involved in anti-inflammatory processes. By balancing these responses, EA effectively mitigates allergic and inflammatory conditions (37). Additionally, in a rabbit model of intervertebral disc degeneration induced by axial compression, EA applied at the lumbar “Jiaji” acupoints (EX-B2) exhibited notable anti-inflammatory effects. Experimental results demonstrated that EA significantly downregulated the expression of pro-inflammatory cytokines TNF-α and IL-1β in nucleus pulposus tissue, while also suppressing the secretion of senescence-associated secretory phenotype (SASP) factors such as IL-6 and IL-8 (38). These findings suggest that EA, as a non-surgical treatment modality, may provide a potential therapeutic approach for mitigating LF thickening in LSS by modulating inflammatory factors.

The NF-κB pathway is a pivotal signaling mechanism crucial for the initiation and regulation of inflammatory responses. By activating pro-inflammatory cytokines such as IL-1 and TNF-α, NF-κB governs the expression of a suite of pro-inflammatory genes, including cytokines, chemokines, and adhesion molecules. This modulation of immune cell functions amplifies the inflammatory response. Furthermore, NF-κB enhances cell survival by suppressing apoptosis-related gene expression, enabling cells to endure stress. Notably, NF-κB has a complex dual role: it promotes both inflammatory responses and, under certain conditions, anti-inflammatory processes that resolve inflammation (34, 39–41). Studies indicate that EA can inhibit the excessive activation of the NF-κB signaling pathway. EA significantly diminished the expression of pro-inflammatory cytokines such as TNF-α and IL-1β, while modulating anti-inflammatory cytokines like IL-10, thereby exerting anti-inflammatory effects (35). Importantly, pro-inflammatory cytokines like TNF-α and IL-1β, along with IL-10, activate downstream signaling pathways, culminating in the activation of the IκB kinase (IKK) complex. This complex primarily comprises IKKα, IKKβ, and IKKγ (NEMO). IKKβ phosphorylates inhibitor of κB (IκB) proteins, which bind to NF-κB, preventing its translocation from the cytoplasm to the nucleus. The degradation of IκB releases NF-κB, enabling it to enter the nucleus and activate the transcription of target genes (41–43). This intricate regulatory pathway drives the persistence and amplification of inflammatory responses. WU et al. (42) demonstrated that EA effectively downregulates inflammatory factors IL-1β, IL-6, and TNF-α in a knee osteoarthritis model, mitigating cartilage degeneration by modulating the NF-κB signaling pathway. Specifically, EA regulates the inflammatory response by inhibiting IKK-β and NF-κB p65 expression while upregulating IκB-α levels, thereby protecting articular cartilage and improving joint function. These findings provide vital molecular evidence supporting the use of EA in treating osteoarthritis, highlighting its potential efficacy in reducing inflammation and preserving joint tissue. In addition, Xia et al. (44, 45) demonstrated that 2 Hz EA significantly suppressed the expression of high mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and NF-κB p65 proteins in both the spinal cord and dorsal root ganglion in a spared nerve injury (SNI)-induced neuropathic pain rat model. EA also reduced the co-expression of microglial marker CD11b with TLR4/MyD88.By modulating the HMGB1/TLR4/NF-κB signaling pathway, EA effectively attenuated neuroinflammatory responses and mechanical hypersensitivity. Therefore, the anti-inflammatory effects of EA observed in these studies, specifically its downregulation of the HMGB1/NF-κB pathway, suggest its potential therapeutic value for conditions like LSS, where similar NF-κB-mediated inflammation is implicated in LF pathology.

The JAK/STAT signaling pathway, an extensively expressed intracellular signaling cascade, comprises Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Activation of this pathway occurs when cytokines or growth factors bind to their respective receptors, leading to receptor phosphorylation by JAKs and the subsequent recruitment of STAT proteins. These STAT proteins then dimerize and translocate to the nucleus, where they regulate the expression of genes involved in immune responses, cell proliferation, differentiation, and apoptosis. The JAK/STAT pathway is pivotal in inflammatory responses, as its activation modulates the expression of genes related to inflammation, thereby influencing immune modulation and cellular functions (46–48). This pathway mediates the signaling of several cytokines, including interferons (IFNs) and certain interleukins. Research has demonstrated that EA can effectively modulate inflammatory responses by influencing the JAK/STAT pathway. Evidence indicates that EA can effectively modulate inflammatory responses by targeting the JAK/STAT pathway. The anti-inflammatory effects of EA are closely linked to its ability to regulate specific receptors and downstream signaling molecules within this cascade. A compelling series of studies by Wang et al. demonstrated that in a spared nerve injury (SNI) model, 2 Hz EA treatment significantly upregulated the expression of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) in the dorsal root ganglion and spinal cord. This α7nAChR activation subsequently suppressed the phosphorylation of JAK2 and STAT3, as well as rebalanced the levels of pro-inflammatory (IL-1β, IL-6) and anti-inflammatory (IL-10) cytokines (49, 50). Crucially, intrathecal administration of the α7nAChR antagonist α-bungarotoxin reversed both the analgesic effects of EA and its inhibition of JAK2/STAT3/IL-6 signaling (50), underscoring the centrality of this mechanism in EA-mediated anti-inflammatory action. This suggests that in LSS, EA might similarly attenuate local inflammation via the α7nAChR-JAK2/STAT3 axis, potentially providing a molecular basis for reducing LF thickening. Furthermore, work by YAN et al. (51) showed that EA treatment significantly downregulated the mRNA expression of Interleukin-22 (IL-22), JAK2, and STAT3, and suppressed the levels of their phosphorylated proteins (p-JAK2, p-STAT3) in the nucleus pulposus tissue of a rat model of cervical intervertebral disc degeneration (CIDD). These findings indicate that EA mitigates cell apoptosis and inflammatory responses by inhibiting the IL-22/JAK2-STAT3 signaling pathway, thereby conferring protection against intervertebral disc degeneration.

The MAPK signaling pathway is a critical cellular signal transduction mechanism, conserved across a range of organisms, including yeast and mammals. This pathway orchestrates cellular responses to external stimuli through a series of cascade reactions and plays a role in various physiological processes such as cell growth, differentiation, proliferation, and apoptosis. It is mainly comprised of three significant subfamilies: p38 MAPK, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) (52–54). These subfamilies are crucial in cell proliferation, differentiation, apoptosis, and stress responses, and also act as key mediators in inflammatory processes. Studies have shown that EA can inhibit the activation of p38 MAPK and ERK, thereby alleviating inflammation and pain. Specifically, EA suppresses the activation of p38 MAPK, which leads to a decrease in the release of inflammatory mediators. Since ERK activation is closely linked to cell proliferation and survival, EA modulates the phosphorylation state of ERK to influence inflammatory responses (53). Wu et al. demonstrated that suppressing ERK1/2 activation produces direct anti-fibrotic outcomes in LF fibroblasts, reversing the overproduction of ECM proteins that constitutes the primary scaffold of LF thickening (55). According to Fang et al. (56) demonstrated that EA effectively modulates the ERK1/2 signaling pathway in an inflammatory pain model, thereby reducing pain sensitivity. EA suppresses the activation of ERK1/2, resulting in decreased expression of inflammatory factors like COX-2 and neurokinin-1 (NK-1), which in turn affects the binding activity of the downstream transcription factor cAMP(cyclic adenosine monophosphate) response element-binding protein (CREB). In a rat model of acute inflammatory pain induced by complete Freund’s adjuvant (CFA), EA treatment elevated the mechanical paw withdrawal threshold and reduced ankle swelling, mechanistically associated with the downregulation of phosphorylated p38 MAPK (p-p38), its downstream transcription factor activating transcription factor 2 (ATF-2), and the pain receptor vanilloid receptor 1 (VR-1) in the spinal dorsal horn (57) Furthermore, in a model of pain chronification, EA demonstrated a capacity to prevent the transition to chronic pain by attenuating the expression of spinal p38 MAPK and the pivotal pro-inflammatory cytokine TNF-α (58) Critically, chronic inflammation is a well-known precursor to tissue fibrosis. As MAPK pathway activation has been established as a pivotal mechanism driving LF hypertrophy in LSS through pro-inflammatory and pro-fibrotic processes (59), we hypothesize that its targeted inhibition by EA may attenuate this structural pathology, offering a therapeutic strategy that addresses the underlying disease mechanism.

Table 1 provides a comprehensive summary of the key preclinical studies elucidating EA’s modulation of these anti-inflammatory signaling pathways.