1) Search site: Articles are forming PubMed, a database of papers on biomedical science. 2) Database: MEDLINE. 3) Keywords: IL-1β, tendinopathy, tendon disorders, inflammation, mechanisms. 4) Boolean algorithm: (“IL-1β”) OR (“Tendinopathy” OR “Tendon disorders”). 5) Retrieval timeframe: the articles we mainly searched for were published between 2015 and 2025. When referring to classic literature to describe the basic mechanisms, the publication time of these studies was before 2015, but did not exceed 20% of the publication time of the cited literature.

Persistent inflammation is now recognized as a fundamental driver of tendinopathy pathogenesis, orchestrated by dynamic crosstalk between three interconnected cellular compartments: the stromal (tenocytes, tendon stem/progenitor cells), immune-sensing (resident macrophages, mast cells), and infiltrating (recruited immune cells) compartments. Rather than a transient response, inflammation in tendinopathy reflects a dysregulated, self-sustaining network that disrupts tendon homeostasis (42). Within this network, the cytokine IL-1β emerges as a critical signaling node, mediating a feed-forward inflammatory cascade that engages all three compartments and propagates chronicity (43).

The inflammatory cascade in tendinopathy is frequently initiated within the immune-sensing compartment, where resident mast cells and macrophages recognize microdamage or other pathological stimuli via pattern recognition receptors. Upon activation, these cells release IL-1β, which subsequently acts on both infiltrating immune cells and local stromal components. A central pathogenic mechanism is the capacity of IL-1β to polarize macrophages toward a pro-inflammatory M1 phenotype. These M1 macrophages further amplify IL-1β production and recruit additional immune cells, establishing a self-sustaining inflammatory loop that contributes to chronic tendon degeneration (44). However, the influence of IL-1β on M2 macrophages—a phenotype generally associated with anti-inflammatory and reparative functions—is less clearly defined. Whether IL-1β suppresses M2 differentiation, alters the functional properties of existing M2 macrophages, or disrupts the balance between M1 and M2 populations represents a significant knowledge gap. Elucidating these mechanisms will be essential for understanding the dysregulated repair processes in tendinopathy. Future studies should aim to clarify the temporal and contextual effects of IL-1β on macrophage. Most critically, IL-1β directly reprograms the stromal compartment, driving tenocytes into an activated, pro-inflammatory state (45–47). This phenotypic shift is not merely a passive response but represents a fundamental change in tenocyte identity and function. Evidence from human studies indicates that tenocytes from tendinopathic tissues exhibit a sustained activated phenotype, characterized by elevated expression of markers like podoplanin (PDPN) (45). Notably, this inflammatory memory can persist long-term, as tenocytes isolated from patients’ years after clinical intervention display heightened sensitivity to IL-1β challenge, secreting elevated levels of IL-6 and IL-8. This suggests that IL-1β exposure can epigenetically imprint a hyper-responsive state on tenocytes, a potential mechanism for disease chronicity and recurrence (45). At the molecular level, the sustained inflammatory phenotype is underpinned by constitutive activation of the NF-κB pathway (48). IL-1β signaling robustly activates NF-κB, which not only drives the immediate expression of classic inflammatory mediators (IL-6, IL-8, COX-2, PGE-2) but also appears to lower the threshold for subsequent activation, thereby sensitizing tenocytes (49). Inhibition of NF-κB potently reduces IL-1β-induced cytokine production, confirming its central role (50). Furthermore, IL-1β orchestrates a multi-faceted attack on tendon homeostasis by upregulating prostaglandin E synthase (mPGES) and specifically enhancing the expression of the EP4 receptor for PGE2, creating an autocrine loop that may amplify inflammatory and catabolic signals (50–52). The cytokine also stimulates the release of nociceptive mediators like Substance P, directly linking the inflammatory process to pain (53). The cycle of chronicity is further reinforced by IL-1β’s impact on immune cell recruitment (54). By inducing tenocytes to produce chemokines such as CCL20 and CCL5, IL-1β facilitates the recruitment and activation of T cells. These activated T cells reciprocally produce TNF-α and IL-1β, which further activate tenocytes, establishing a vicious paracrine loop that is difficult to resolve (55). This T cell-tenocyte crosstalk not only perpetuates inflammation but also directly contributes to pathological matrix remodeling, as evidenced by an increased collagen III/I ratio (56).

Collectively, IL-1β is a critical node connecting the three cellular compartments and driving chronic inflammation in tendinopathy. It sustains M1 macrophage polarization through a positive feedback loop, induces and maintains the activated inflammatory phenotype of tenocytes, and promotes T cell-mediated immune responses. Future therapeutic strategies could focus on targeting this cytokine network, particularly disrupting the chronic inflammatory state maintained by the IL-1β/NF-κB axis, potentially offering new avenues for the fundamental treatment of tendinopathy (Figure 5).

The progressive degradation of the extracellular matrix (ECM) is a hallmark of degenerative tendinopathy, with matrix metalloproteinases (MMPs) serving as central executors of ECM catabolism (57). A substantial body of evidence indicates that the pro-inflammatory cytokine IL-1β acts as a primary upstream regulator of MMP expression in tenocytes, thereby disrupting ECM homeostasis. Rather than merely cataloging individual findings, this section synthesizes the mechanistic pathways through which IL-1β drives pathological matrix remodeling and examines its critical interplay with mechanical stimuli—a relationship that underpins a self-perpetuating cycle of tendon degeneration.

IL-1β exerts its catabolic effects by shifting the delicate balance between MMPs and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) (58). In healthy tendons, TIMP levels predominate, ensuring controlled turnover. However, upon IL-1β stimulation, tenocytes from multiple species exhibit a coordinated upregulation of key collagenases and stromelysins—notably MMP-1, MMP-3, and MMP-13—without a commensurate increase in TIMP-1 or TIMP-2 (59, 60). This selective induction creates a proteolytic imbalance favoring net matrix degradation. Mechanistically, IL-1β signaling converges on several key pathways: binding to the IL-1 receptor activates the JNK/SAPK and broader MAPK cascades (ERK1/2, p38, JNK), which are requisite for maximal MMP transcription (61, 62). The pathological relevance of this axis is further underscored by the ability of IL-1Ra to attenuate collagen breakdown, albeit at a higher concentration due to competitive receptor binding (63). A particularly insightful concept emerging from the literature is the positive feedback loop initiated by IL-1β. Beyond directly inducing MMPs, IL-1β can stimulate tenocytes to produce more endogenous IL-1β, thereby amplifying and prolonging the catabolic signal (9). This autocrine/paracrine loop may explain the progressive nature of tendinopathy even after the initial insult has subsided. Furthermore, the relative potency of IL-1β compared to other cytokines like TNF-α suggests a specialized role: while TNF-α may initiate degradation, IL-1β appears more critical for driving its progression, as evidenced by its superior capacity to upregulate MMP-3 and MMP-13 in ex vivo models (64).

Perhaps the most significant advance in understanding IL-1β’s role in tendinopathy lies in its integration with the condition’s biomechanical etiology (65). Mechanical overload, a primary risk factor, is no longer viewed as merely causing structural fatigue, but as a trigger for a complex biologic response (66). In this context, tenocytes function as key mechanosensory units that transduce mechanical stimuli into molecular signals, modulating ECM synthesis and degradation to establish novel homeostatic setpoints adapted to their mechanical environment (67). This mechanoresponsive capacity is governed by the cytoskeletal architecture and its dynamic interactions with the ECM (68), where α-smooth muscle actin (αSMA)-mediated organization generates intrinsic cellular tension (69). This tension propagates to the ECM as contractile traction forces, establishing a biomechanical equilibrium within the tissue microenvironment (70). However, pathological overload disrupts this equilibrium: microdamage from overloading relieves mechanical tension on tenocytes, effectively creating a state of “unloading” at the cellular level (71). This aberrant mechanical environment not only stimulates IL-1β production—potentially via mechanisms such as H₂O₂-induced NLRP3 inflammasome activation (72, 73)—but also critically determines cellular responsiveness to the cytokine. It has been reported that tenocytes with diminished intrinsic tension exhibit exaggerated catabolic responses to IL-1β, including markedly increased MMP expression and apoptosis, ultimately leading to ECM destruction (74). Conversely, tenocytes maintaining high cellular tension demonstrate markedly attenuated responses to IL-1β-induced catabolic events (75), establishing cellular tension state as a pivotal regulator of IL-1β-driven pathology.

Emerging evidence further suggests that dysregulation of mechanosensitive signaling pathways, such as the Yes-associated protein (YAP) pathway, may link abnormal mechanical loading to inflammatory and catabolic responses in tenocytes. Under physiological loading, YAP shuttles between the cytoplasm and nucleus to regulate cell proliferation and matrix homeostasis; however, excessive mechanical stress can lead to aberrant YAP activation, which has been associated with pro-inflammatory gene expression and matrix remodeling (76). Although direct crosstalk between YAP and IL-1β in tendinopathy remains underexplored, studies in other musculoskeletal tissues suggest that YAP signaling can modulate IL-1β production and subsequent MMP activation (77). The resulting cytokine surge promotes MMP secretion, degrading the pericellular matrix and further compromising tissue integrity. Thereby, a self-perpetuating vicious cycle is established: mechanical damage induces IL-1β expression and reduces cellular tension, which synergistically promotes ECM breakdown; this degradation, in turn, weakens the tendon structure and increases its susceptibility to additional mechanical injury. Notably, both excessive strain and stress-shielding upregulate IL-1β and MMPs, thereby driving degenerative processes. The magnitude of mechanical stretch plays a decisive role in determining cellular responses: while low-magnitude strain may exert protective or anti-inflammatory effects, high-magnitude strain acts synergistically with IL-1β to markedly upregulate MMP-1 and MMP-3 expression (78). This synergy underscores that mechanical stress and inflammatory signaling are integrated at the molecular level, collectively governing the net catabolic outcome in tendon tissue. Importantly, pharmacological restoration of cytoskeletal tension (e.g., via calyculin A administration (79)) has been shown to reverse IL-1β-driven catabolism by reestablishing physiological tension homeostasis, highlighting targeted modulation of tenocyte mechanobiology as a promising therapeutic strategy for counteracting inflammatory degradation in tendinopathy.

Collectively, these studies firmly establish IL-1β as a master regulator of ECM degradation in tendinopathy, primarily by disrupting the critical balance between MMPs and TIMPs. The interplay between IL-1β and mechanical loading is particularly noteworthy, suggesting a vicious cycle where microdamage from overloading induces IL-1β expression, which in turn promotes further ECM cleavage, weakening the tendon and making it more susceptible to additional damage. Critically, the cellular response to IL-1β is governed by the mechanobiological state of tenocytes: loss of intrinsic cytoskeletal tension following microdamage hypersensitizes cells to IL-1β, exacerbating matrix destruction. Future therapeutic strategies should extend beyond anti-inflammation to target this mechanobiological dysregulation. Elucidating the crosstalk between pathways like YAP and IL-1β signaling, and developing interventions to “re-tension” tenocytes, hold promise for breaking the degenerative cycle and promoting tendon regeneration.

Beyond the well-established role of tenocytes in tendon homeostasis, the identification of tendon stem/progenitor cells (TSPCs) has fundamentally expanded our understanding of tendon biology and pathology (80). TSPCs, distinct from mature tenocytes, possess the critical capacities for self-renewal and differentiation, serving as a reservoir for tissue maintenance and repair (81). In healthy tendon healing, TSPCs undergo tenogenic differentiation to regenerate functional tissue (82). However, in the pathological microenvironment of tendinopathy, TSPCs are driven toward aberrant differentiation lineages—namely chondrogenic, osteogenic, and adipogenic—leading to the characteristic degenerative features of lipid deposition, proteoglycan accumulation, and ectopic calcification (83). A key insight emerging from recent research is that the cytokine IL-1β acts as a potent pathological switch that redirects TSPC fate away from regeneration and toward degeneration (84).

It has been reported that IL-1β consistently suppresses the expression of key tenogenic markers such as scleraxis (Scx), tenomodulin (Tnmd), and type I collagen, while simultaneously promoting markers of non-tenogenic lineages. What makes this effect particularly consequential for chronic tendinopathy is its potential persistence. Studies indicate that even transient exposure to IL-1β can cause a lasting impairment of TSPCs’ tenogenic potential, suggesting that an early inflammatory insult may irreversibly compromise the tendon’s intrinsic repair capacity long after the initial cytokine signal has subsided (85). This provides a plausible cellular mechanism for the progressive and often irreversible nature of advanced tendinopathy. The mechanistic underpinnings of this fate switch involve multiple signaling pathways. IL-1β has been shown to act through the downregulation of microRNAs such as miR-337-3p, leading to the activation of Nox4-JNK and IRS1-ERK cascades that favor chondro-osteogenic differentiation (86). Other work implicates the Rac1 signaling pathway in IL-1β-mediated induction of osteogenic markers (SOX9, COL2α1) and suppression of tenogenic factors (87). Furthermore, the source of IL-1β is also of pathological relevance. Recent evidence links pyroptotic macrophages—a highly inflammatory form of cell death—to IL-1β release, which in turn drives TSPCs toward osteogenic differentiation, creating a direct bridge between immune cell activity and degenerative tissue remodeling (88).

In summary, the impact of IL-1β on TSPCs represents a critical paradigm shift in tendinopathy pathogenesis. It moves the focus beyond the catabolic degradation of the existing matrix by tenocytes to include the failure of regenerative potential through the maldifferentiation of the progenitor cell pool. This dual attack—simultaneously breaking down mature tissue and corrupting the cells meant to rebuild it—explains the progressive and structurally disastrous nature of the disease. Therefore, therapeutic strategies that not only block IL-1β’s catabolic effects but also safeguard or restore the tenogenic differentiation capacity of TSPCs could be pivotal in achieving true tendon regeneration rather than mere symptom mitigation. Future research should prioritize elucidating the epigenetic mechanisms behind IL-1β’s long-lasting effects on TSPCs and identifying strategies to therapeutically reverse this pathological reprogramming.

Beyond its well-characterized roles in promoting inflammation and matrix degradation, IL-1β contributes to tendinopathy pathogenesis by accelerating tenocyte death through the induction of apoptotic pathways (89). While physiological apoptosis is essential for tissue turnover, its dysregulation represents a critical mechanism of cellular depletion and functional decline in degenerative tendons (90). A growing body of evidence positions IL-1β as a master regulator of this pathological apoptosis, primarily through its orchestration of the NF-κB and PI3K/Akt signaling axes.

The pro-apoptotic effect of IL-1β is executed via the classic mitochondrial pathway, culminating in the activation of caspase-3, the key effector protease of apoptosis. IL-1β signaling shifts the delicate balance between pro-apoptotic and anti-apoptotic proteins, consistently upregulating Bax while suppressing Bcl-2 (91). This imbalance promotes mitochondrial membrane permeabilization, triggering the caspase cascade and committing the cell to death (91). What elevates this finding from a simple observation to a mechanistically insightful one is the identification of the specific signaling pathways involved and their regulatory nodes. Research demonstrates that IL-1β concurrently activates both the NF-κB and PI3K/Akt pathways to drive apoptosis. Notably, the caspase-3-dependent apoptotic process appears specifically tied to NF-κB activation (92). A crucial upstream regulator of this pathway is Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase associated with cellular stress responses (93). IL-1β downregulates SIRT1, which in turn unleashes NF-κB activity, leading to the pro-apoptotic Bax/Bcl-2 dysregulation (93). This mechanistic hierarchy is substantiated by interventional studies: compounds like chitosan and resveratrol can attenuate IL-1β-induced apoptosis by activating SIRT1, thereby suppressing NF-κB signaling and restoring cell survival (92, 94).

In summary, the induction of apoptosis solidifies IL-1β’s role as a central mediator of tendon degeneration. Its ability to activate specific, interconnected pathways like NF-κB and PI3K/Akt, finely tuned by regulators like SIRT1, provides a sophisticated mechanism for excessive cell death. Viewing IL-1β through the lens of apoptosis unveils new therapeutic opportunities aimed at preserving the tenocyte population by targeting these regulatory nodes, potentially slowing disease progression by maintaining the cellular workforce essential for tendon homeostasis.

Of note, cellular senescence has emerged as a pivotal mechanism in tendinopathy, operating in concert with apoptosis to drive tissue dysfunction (95). Senescent cells, characterized by irreversible growth arrest and a distinct secretory phenotype, accumulate in degenerative tendons and contribute to an impaired regenerative environment (96). Key biomarkers of this state include elevated expression of cyclin-dependent kinase inhibitors p16 and p21, tumor suppressor p53, and increased senescence-associated β-galactosidase (SA-β-gal) activity (97). A compelling body of evidence now identifies IL-1β as a potent inducer of this deleterious state in both tenocytes and tendon stem/progenitor cells (TSPCs).

The mechanistic link between IL-1β and senescence is robustly demonstrated across multiple studies. Stimulation with IL-1β reliably triggers a canonical senescent phenotype in tenocytes, manifesting as altered morphology, growth arrest, and upregulated expression of p16, p21, and p53, alongside enhanced SA-β-gal activity (98). A key insight is the central role of the NF-κB signaling pathway in mediating this response. The pathological relevance of this axis is confirmed by interventional data: inhibition of NF-κB signaling effectively attenuates IL-1β-induced senescence markers in TSPCs. Furthermore, the microRNA miR-146a, a known negative regulator of inflammation, has been shown to confer protection against IL-1β-driven senescence by suppressing the upstream IRAK4/TRAF6/NF-κB cascade (99). This not only reinforces the role of NF-κB but also suggests the existence of endogenous regulatory mechanisms that become overwhelmed in the diseased state.

In summary, IL-1β’s capacity to induce cellular senescence solidifies its position as a master regulator of tendon degeneration, acting through a well-defined NF-κB-dependent pathway. This mechanism contributes to the failure of tissue homeostasis not merely by reducing cell numbers, as in apoptosis, but by creating a population of dysfunctional, senescent cells that actively degrade the tissue milieu. Therapeutic strategies aimed at selectively eliminating senescent cells (senolytics) or modulating their secretory phenotype (senomorphics) may therefore hold promise for disrupting this vicious cycle in IL-1β-driven tendinopathy.