Therapeutic mechanisms of icariin in intervertebral disc degeneration: A critical narrative review

Abstract

Intervertebral disc degeneration (IDD), a primary cause of low back pain, involves complex pathological mechanisms. Current research emphasizes identifying strategies to mitigate degenerative processes and enhance intrinsic disc repair. Emerging evidence highlights the therapeutic potential of icariin (ICA) in promoting disc repair and delaying IDD progression. ICA exerts its effects through multiple mechanisms, including anti-inflammatory actions, oxidative stress mitigation, modulation of bone and collagen metabolism, and inhibition of ferroptosis and pyroptosis. This review synthesizes current research on ICA's therapeutic applications in IDD management.

Highlights

• •Icariin (ICA) effectively promotes intervertebral disc repair and slows the progression of intervertebral disc degeneration (IDD).
• •ICA's therapeutic effects are mediated through anti-inflammatory, antioxidative actions, and modulation of bone and collagen metabolism.
• •ICA also suppresses ferroptosis and pyroptosis, enhancing the intrinsic repair mechanisms of intervertebral discs.

1. Introduction

Low back pain represents the leading global cause of disability. In China, chronic low back pain prevalence reaches 31.54 %, with incidence increasing with age. This condition substantially reduces quality of life while imposing significant socioeconomic burdens [1]. IDD constitutes a major etiological factor in low back pain, involving intricate pathological mechanisms and limited capacity for nucleus pulposus regeneration. Current clinical interventions primarily focus on symptomatic relief, often resulting in recurrence and high treatment costs [2]. Consequently, developing approaches to reverse degeneration and stimulate endogenous disc repair remains crucial for effective treatment [3].

In traditional Chinese medicine (TCM), low back pain falls under the category of “lumbar bi.” Classical texts such as Mai Yao Jing Lun attribute lumbar pain to kidney deficiency, stating, “The waist is the house of the kidney; kidney essence depletion leads to restricted movement.” TCM emphasizes kidney tonification to restore bone-marrow nourishment and mitigate degeneration [4,5]. Modern pharmacological studies validate the efficacy of TCM compounds, particularly ICA—a bioactive flavonoid from Epimedium—in IDD management [6].

2. Literature search and selection criteria

A systematic literature search was conducted using PubMed, Web of Science, CNKI, and Google Scholar for articles published between 2000 and 2025. Keywords included “icariin,” “intervertebral disc degeneration,” “anti-inflammatory,” “oxidative stress,” “ferroptosis,” and “pyroptosis.” Inclusion criteria: (1) studies focusing on ICA's mechanisms in IDD; (2) in vitro, in vivo, or clinical research; (3) English or Chinese publications. Exclusion criteria: (1) studies unrelated to ICA or IDD; (2) non-peer-reviewed articles (e.g., conference abstracts); (3) duplicated datasets. Initial searches yielded 327 articles, with 68 retained after screening titles/abstracts and 55 included after full-text review. Limitations included heterogeneous experimental models (e.g., varying animal species, cell types, and ICA dosages) and small sample sizes in some studies. Contradictions emerged regarding ICA's concentration-dependent effects on matrix synthesis, which were critically discussed to contextualize findings. Future studies standardizing protocols and validating outcomes in larger cohorts are warranted.

3. The source and biological activity of ICA

Epimedium [7], derived from the dried leaves of this medicinal plant, was first documented in Shennong's Classic of Materia Medica. Characterized by a pungent, sweet, and warm nature, it primarily acts on the liver and kidney meridians in TCM. This botanical agent demonstrates triple therapeutic effects: nourishing kidney yang, strengthening musculoskeletal integrity, and eliminating wind-dampness pathologies, establishing its pivotal role in TCM-based management of low back pain. The predominant bioactive constituent, ICA(C₃₃H₄₀O₁₅, MW676.66), undergoes hepatic metabolism to generate pharmacologically active metabolites including icaritin, icarisides I/II, and desmethylicaritin [8]. Emerging evidence from preclinical studies reveals icaritin's multimodal bioactivities: neurotrophic effects through neuronal growth promotion and cytoprotection, osteometabolic modulation, dual anti-inflammatory/antioxidant capacities, and pleiotropic regulation of cellular signaling cascades [9]. Notably, ICA exerts skeletal-protective effects manifested by increased bone mineral density and accelerated regeneration of osseous/cartilaginous tissues post-injury [10,11].

4. Pathological mechanisms of IDD

The intervertebral disc comprises three structural components: the outer annulus fibrosus, inner nucleus pulposus, and cartilaginous endplates. This fibrocartilaginous structure facilitates spinal mobility while maintaining stability through pressure absorption and load distribution [12]. IDD progression features gradual tissue dehydration, biomechanical failure, chronic inflammation, and extracellular matrix (ECM) degradation mediated by upregulated matrix metalloproteinases (MMPs). The degenerative cascade creates a self-perpetuating cycle of inflammatory cell infiltration, pro-inflammatory cytokine release, and accelerated tissue breakdown [13]. Currently, clinical treatment focuses on pain relief and improving symptoms and function, but effectively restoring intervertebral discs remains a major challenge. Previous studies have shown that tissue engineering-based biological repair methods, such as hydrogels and scaffolds, have significant benefits, although they still face some limitations.

5. Therapeutic mechanisms of ICA(Table 1, Table 2 and Fig. 1)

Table 1.

Summary of the in vitro researches about pharmacological activities of ICA in IDD.

Type of model	Dose	Findings	Conclusions	Reference
Human chondrocytes C28/I2	50,100,150,μg·mL-1 ICA	TNF-α↓, IL-6↓,IL-8↓	ICA exhibits a significant inhibitory effect on autophagy and the inflammatory response, and this mechanism is likely attributable to the attenuation of the NF-κB pathway	20
New Zealand rabbits BMSCs	0.01, 0.1, 1 and 10 μmol/L ICA	Alkaline phosphatase activity↑, the number of Calcified nodules↑	ICA could promote the proliferation of BMSCs and differentiation of BMSCs into osteogenesis	29
New Zealand rabbits BMSCs	0,0.1,1, and 10 μM ICA	the cartilage differentiation of BMSCs↑, cell proliferation of BMSCs↑, type II collagen↑,BMP2↑	The co-administration of ICA and BMSCs can facilitate the repair of rabbit knee cartilage injuries through the modulation of the BMP/Smads pathway	30
Rat calvarial osteoblasts (ROB)	1 × 10−4,1 × 10−5, 1 × 10−6 and 1 × 10−7 mol/L ICA	BMP-2↑,RUNX-2↑,Osterix↑	ICA can enhance the expression of osteogenic markers of ROB	33
SD rats NP cells	10,20,40 μmol/L ICA	Proliferation rate of NP cells↑,IL-1β↓,IL-6↓, The mRNA and protein expression levels of Aggrecan and CollagenⅡ↑	ICA can delay the degeneration of intervertebral disc	36
SD rats BMECs	34 mg L−1 ICA	the cell viability↑,GSH↑,SOD↑,ROS↓ MDA↓, ferrous ion↓	ICA can inhibit steroid-induced BMECs ferroptosis, the mechanism may be associated with the inhibition of ferroptosis by regulating autophagy.	45
SD rats chondrocytes	100 μmol/L ICA	NRLP3↓,IL-1β↓,IL-18↓,MMP-1↓,MMP-13↓,Caspase-1↓,ASC↓, GSDMD↓Collagen↑	ICA prevents lipopolysaccharide-induced chondrocyte damage and degradation by suppressing the NLRP3 and Caspase-1 signaling pathways	50

Table 2.

Summary of the in vivo researches about pharmacological activities of ICA in IDD.

Type of model	Route	Dose	Duration	Findings	Reference
SD rats IDD model by nucleus pulposus aspiration	gavage	25,50,100mg/(kg·d) ICA	6 weeks	IL-1β↓ IL-6↓	36
Rabbits IDD model by nucleus pulposus aspiration	gavage	3mg/(kg·d) ICA	4 weeks	typeⅡcollagen↑ proteoglycan↑	37
Wistar rats IDD model by fiber ring puncture	lavage	6g/(kg·d) ICA	8 weeks	typeⅡcollagen↑ MMP mRNA↓	38

Fig. 1.

Effects of ICA in IDD.

5.1. Anti-inflammatory effects

A bidirectional pathogenic relationship exists between IDD and the inflammatory response. Exaggerated inflammatory activation within nucleus pulposus tissue has been mechanistically linked to accelerated degenerative progression [14]. During IDD pathogenesis, nucleus pulposus cells progressively upregulate secretion of pro-inflammatory cytokines such as tumor necrosis factor-α(TNF-α), interleukin-1α(IL-1α), IL-1β, and IL-6. These inflammatory mediators disrupt ECM homeostasis through dual mechanisms: initiating catabolic cascades while concomitantly activating immune cell recruitment. The self-perpetuating inflammatory milieu compromises ECM integrity via transcriptional suppression of critical structural macromolecules such as type II collagen and proteoglycans— key determinants of disc biomechanical competence. Furthermore, cytokine-mediated induction of MMPs and allied degradative enzymes exacerbates disc matrix breakdown. Notably, chronic inflammation synergistically promotes autophagy dysregulation, cellular senescence, and apoptosis, thereby driving multidimensional amplification of IDD pathogenesis [15].

ICA exerts immunomodulatory effects via NF-κB/NLRP3 pathway inhibition, reducing IL-1β, IL-6, and TNF-α levels in degenerative disc models [16,17]. In LPS-induced endometritis models, ICA treatment (10 mg/kg) significantly attenuated inflammatory cell infiltration while elevating anti-inflammatory IL-10 expression [18]. The compound's antioxidant capacity was evidenced by normalization of oxidative stress markers—including malondialdehyde (MDA) and reactive oxygen species (ROS) —alongside restoration of antioxidant enzyme activities (SOD1, CAT, GPx 1). In a stratified experimental design employing IL-1β-stimulated C28/I2 chondrocytes, ICA treatment (low/medium/high doses) counteracted cytokine-induced cytotoxicity, reversed TNF-α/IL-6/IL-8 elevation, and mitigated autophagy protein overexpression — with therapeutic effects exhibiting dose-response characteristics. These findings collectively establish ICA's capacity to orchestrate multi-target inhibition of NF-κB signaling, thereby concomitantly reducing inflammatory burden, preserving chondrocyte viability, and modulating autophagy dysregulation [19].

5.2. Oxidative stress mitigation

The pathophysiological hallmarks of intervertebral disc degeneration (IDD) include progressive cellular depletion and extracellular matrix (ECM) depletion mediated by apoptotic cascades [20]. Notably, oxidative stress constitutes a pivotal pathogenic driver in this degenerative continuum, acting synergistically with cytokine signaling and biomechanical overload to initiate apoptosis. This oxidative milieu potentiates inflammatory activation within disc tissue via multi-pathway stimulation, resulting in upregulation of matrix-degrading enzymes and consequent disruption of ECM anabolism/catabolism equilibrium. Such homeostatic imbalance structurally compromises disc integrity, thereby establishing a self-reinforcing degenerative cycle [21]. Histopathological analyses by Lyu et al. [22] revealed significant overexpression of inflammatory mediators in degenerative disc tissues, with IL-17 A emerging as a master regulator of disc inflammation. Mechanistically, IL-17 A orchestrates pro-inflammatory cascades through concurrent activation of NF-κB and MAPK pathways, driving transcriptional upregulation of IL-2, IL-6, COX-2, PGE2, and TNF-α—key amplifiers of inflammatory pathology in degenerative discs [23].

The pharmacological profile of Epimedium encompasses tripartite therapeutic actions: anti-inflammatory modulation, redox homeostasis restoration, and apoptosis inhibition. ICA has demonstrated the ability to alleviate oxidative stress and protect cells from oxidative damage by enhancing the production of antioxidant enzymes. ICA enhances cellular antioxidant defenses by activating Nrf2/Txnip/Trx signaling, thereby suppressing ROS/MDA accumulation in spinal cord injury models. Dose-dependent experiments revealed ICA's capacity to restore redox balance through SOD/GSH upregulation [24,25]. Molecular interrogation via immunofluorescence revealed ICA's dual regulatory effects: upregulation of Trx coincident with suppression of Txnip and NLRP3 expression. These molecular insights collectively suggest that ICA exerts cytoprotective effects through coordinated modulation of the Nrf2/Txnip/Trx-NLRP3 axis, simultaneously counteracting oxidative stress and inflammatory signaling.

5.3. Bone metabolism regulation

The interplay between IDD and skeletal metabolism manifests through bidirectional pathological crosstalk. Biomechanical decompensation secondary to disc deterioration induces aberrant stress distribution across spinal joints, disrupting physiological bone remodeling and predisposing to osteoporosis and osteophyte formation. Conversely, metabolic bone disorders — particularly estrogen-deficient osteoporosis—may exacerbate IDD progression through matrix homeostasis dysregulation. Notably, IDD-associated inflammation amplifies osteoclastogenesis, thereby skewing the bone remodeling equilibrium toward excessive resorption. Extensive research has indicated that ICA can enhance osteoblast activity while concurrently inhibiting osteoclast formation, thereby promoting bone formation and improving bone mineral density [26,27]. Bone marrow mesenchymal stem cells (BMSCs) exhibit robust proliferative capabilities and possess the potential for multilineage differentiation, allowing them to differentiate into osteoblasts and chondrocytes, thus playing a crucial role in the repair of bone and cartilage. In controlled dose-temporal experiments by Li et al. [28], rabbit-derived BMSCs exhibited concentration-dependent proliferative responses to ICA, achieving peak cellular proliferation and osteogenic differentiation at 1 μmol/L within 48 h. Complementarily, Jiao et al. [29] established ICA's chondroprotective efficacy in articular cartilage injury models, demonstrating dose-responsive enhancement of BMSC chondrogenesis concomitant with upregulated collagen II and BMP2 expression — key biomarkers of cartilage regeneration.

Zhou et al. reported that [30] ICA, functioning as a phytoestrogen, may activate estrogen receptors by enhancing the rapid induction of IGF-1 signaling in osteoblasts, thereby promoting bone formation. Research has further demonstrated that elevated concentrations of ICA can stimulate the differentiation and maturation of osteoblasts while inhibiting bone resorption, ultimately enhancing the regenerative capacity of both bone and cartilage [31]. ICA stimulates osteoblast differentiation via IGF-1/BMP/Smad pathways while inhibiting osteoclastogenesis. At 1 μmol/L, ICA optimally enhanced BMSC proliferation and osteogenic marker expression (BMP-2, RUNX-2) in 3D collagen hydrogels [32].

5.4. Collagen homeostasis

Collagen is a fundamental component of the intervertebral disc, primarily located in the annulus fibrosus and nucleus pulposus [33]. Its presence is essential for maintaining the structural integrity of the intervertebral disc, contributing to its elasticity and ability to withstand external compressive forces. Consequently, the regulation of collagen metabolism is critical for the stability of the intervertebral disc. The pathogenesis of IDD is closely linked to disrupted collagen homeostasis, which is characterized by an imbalance between anabolic and catabolic processes. Recent studies suggest that this metabolic dysregulation is mediated by three key regulatory pathways: (1) regulators of collagen biosynthesis, including synthetic enzymes, growth factors, and associated regulatory proteins; (2) collagenolytic enzymes, particularly MMPs and cysteine proteinases; and (3) inflammatory mediators, which encompass both pro-inflammatory and anti-inflammatory cytokines. Collectively, these molecular factors orchestrate a complex regulatory network that governs collagen synthesis and degradation within the microenvironment of the intervertebral disc [34]. ICA administration (3–6 mg/kg/day) significantly upregulated type II collagen and aggrecan expression in rat IDD models, concurrently suppressing MMP-mediated ECM degradation [[35], [36], [37]].

5.5. Ferroptosis inhibition mechanisms

Ferroptosis, an iron-dependent regulated cell death modality, is characterized by lethal lipid peroxide accumulation through two core biochemical processes: (1) intracellular iron overload and (2) iron-catalyzed peroxidation of membrane polyunsaturated fatty acids. Morphological hallmarks include mitochondrial atrophy with increased membrane density and cristae reduction, while maintaining intact plasma membranes, normal nuclear morphology, and absence of chromatin condensation [38]. Emerging evidence confirms ferroptosis involvement in IDD pathogenesis. The cartilage endplate—the primary nutrient supply conduit for discs—undergoes degenerative calcification that disrupts biomechanical stability and nutrient diffusion [39]. Wang et al. demonstrated that oxidative stress and iron overload accelerate cartilage endplate cell mineralization, inducing mitochondrial dysfunction and IDD progression. The glutathione peroxidase 4 (GPX4)-glutathione (GSH) axis constitutes a critical antioxidant defense system, where GPX4 enzymatically neutralizes lipid peroxides using GSH as cofactor [40]. Yao et al. identified BACH1-mediated GPX4 suppression as a mechanism promoting oxidative stress and nucleus pulposus denervation through ferroptosis induction [41]. In tert-butyl hydroperoxide-induced oxidative stress models, elevated protein/lipid peroxidation markers correlated with disc cell degeneration, whereas ferroptosis inhibitors significantly attenuated IDD progression [42].

Zhu et al. [43] reported that following IDD, levels of Sirt3 (silent regulatory protein 3) decreased, leading to ferroptosis in cells. They utilized USP11 (ubiquitin-specific protease 11) to deubiquitinate and stabilize Sirt3, thereby reducing oxidative stress and inhibiting cell ferroptosis, which in turn alleviated IDD. Several studies have established a ferroptosis model in rat bone microvascular endothelial cells (BMECs) through hormonal intervention, and subsequent intervention with ICA demonstrated significant improvements in cell viability, as well as increased levels of GSH (glutathione) and SOD (superoxide dismutase) compared to the hormone group. Additionally, the ICA group exhibited reduced levels of ROS (reactive oxygen species), MDA (malondialdehyde), and ferrous ions relative to the hormone group. These results indicate that ICA enhances the antioxidant capacity of cells and inhibits ferroptosis in BMECs [44]. Through comprehensive mechanistic studies, Xiao and colleagues have shown that ICA provides chondroprotective effects by mitigating ferroptosis in chondrocytes and reducing articular cartilage degeneration. Their findings suggest that the protective effects of ICA are mediated through multiple molecular mechanisms, including (1) activation of the SLC7A11/GPX4 antioxidant signaling axis, (2) restoration of extracellular matrix homeostasis via upregulation of type II collagen expression, (3) enhancement of chondrogenic differentiation capacity through modulation of the SOX9 transcription factor, and (4) significant reduction of oxidative stress markers, such as intracellular ROS, lipid peroxides, and MDA levels [45].

5.6. Pyroptosis inhibition mechanisms

Pyroptosis, a pro-inflammatory programmed cell death modality, manifests distinctive morphological features including cellular swelling, plasma membrane rupture, and release of intracellular contents that amplify inflammatory cascades. This process is mechanistically governed by inflammatory caspases and gasdermin (GSDM) protein activation. The canonical pathway for the activation of pyroptosis plays a significant role in the pathophysiology of IDD. The primary mechanisms involve the initiation of cell death in nucleus pulposus cells, leading to disorganized degradation of the extracellular matrix of the intervertebral disc and the induction of secondary inflammation in surrounding tissues. This underscores the necessity of comprehending and potentially modulating pyroptosis in relation to intervertebral disc health and disease [46]. Research has identified that the pyroptosis-related genes associated with IDD predominantly include members of the NOD-like receptor pyrin domain-containing protein family, the caspase family, IL-1β, and GSDMA, among others. During the progression of IDD, nucleus pulposus cells continuously secrete a significant quantity of pro-inflammatory cytokines, with TNF-α and IL-1β being the most notable [47]. Zhang et al. [48] demonstrated that the inhibition of elevated expression levels of key apoptotic proteins, such as Bax, Caspase-3, IL-1β, and P53, can delay apoptosis in intervertebral disc tissue and impede the progression of IDD. Furthermore, Shi et al. reported that the expression levels of pyroptosis-related proteins, including IL-1β, IL-18, MMP-1, MMP-13, NLRP3, Caspase-1, and GSDMD, were significantly reduced following the administration of ICA (100 μmol/L) in a chondrocyte model (P < 0.05), suggesting that ICA effectively inhibits pyroptosis in cells and, consequently, inflammation [49].

A growing body of evidence has highlighted the critical role of NLRP3 inflammasome activation in the pathogenesis of IDD. Mechanistic investigations indicate that the activation of the NLRP3 inflammasome triggers a series of pathological events, wherein the resulting inflammatory mediators further exacerbate degenerative processes within the intervertebral disc. The activated NLRP3 inflammasome complex primarily orchestrates various pathological mechanisms involved in the progression of IDD, including (1) sustained inflammatory responses, (2) pyroptotic cell death, (3) degradation of the extracellular matrix, and (4) apoptosis of disc cells, all of which contribute to the degenerative cascade [50].

The NLRP3 inflammasome is recognized as a pivotal effector molecule in the process of pyroptosis [51]. Inhibition of NLRP3 inflammasome-mediated pyroptosis has been shown to mitigate the degradation of type II collagen, thereby potentially delaying the progression of IDD [52]. In a study [53]conducted by Zeng et al., a rat model of focal cerebral ischemia-reperfusion was subjected to continuous administration of ICA at dosages of 20 mg/kg, 40 mg/kg, and 80 mg/kg. The results indicated a significant reduction in the expression of IL-1β and IL-18 positive cells in the ICA-treated group compared to the control group. Furthermore, the protein levels of NLRP3, ASC, and Caspase-1 were markedly decreased in the ICA group, with statistical significance noted at P < 0.01 and P < 0.05, respectively. The NLRP3 inflammasome is a multi-protein complex composed of NLRP3, ASC, and the Caspase-1 precursor. These findings imply that ICA may effectively inhibit the NLRP3 inflammasome signaling pathway, thereby attenuating the inflammatory response [54].

6. Future perspectives

ICA has emerged as a promising therapeutic option for IDD, yet several critical gaps in current research must be bridged to facilitate its clinical translation.

6.1. Mechanistic elucidation

Despite ICA's demonstrated therapeutic potential, the precise molecular mechanisms underlying its actions remain incompletely defined. Conflicting data across studies regarding its modulation of specific signaling pathways—such as NF-κB versus MAPK—underscore the urgent need for standardized experimental models and systematic pathway analyses to resolve these discrepancies and clarify context-dependent effects.

6.2. Clinical validation

While preclinical studies in animal models have shown efficacy, these results have not been consistently replicated in human trials. To address this translational gap, rigorous, multi-center clinical trials are essential. These studies should focus on establishing standardized treatment protocols, validating therapeutic efficacy across diverse patient populations, and assessing long-term safety profiles and optimal dosing regimens.

6.3. Formulation optimization

ICA's poor water solubility and low bioavailability pose significant challenges for effective delivery. Emerging strategies, such as combining ICA with hydrogel scaffolds or nanoparticle carriers, show promise in enhancing its therapeutic index. However, further optimization of these formulations is required to maximize delivery efficiency and minimize off-target effects.

6.4. Synergistic combinations

Exploring combinatorial therapies, such as pairing ICA with matrix-modifying agents, could potentially amplify therapeutic outcomes. However, this approach necessitates thorough investigation into potential drug-drug interactions and pharmacokinetic alterations to ensure safety and efficacy.

6.5. Pharmacological interactions and safety profile of ICA

Current evidence on ICA's interactions with other medications or chronic toxicity remains sparse in IDD-specific studies. However, existing pharmacokinetic data suggest that ICA undergoes hepatic metabolism via cytochrome P450 enzymes (e.g., CYP3A4), raising potential interactions with drugs metabolized through these pathways (e.g., statins or anticoagulants). Preclinical studies in osteoarthritis models report low systemic toxicity with prolonged ICA administration, though high-dose regimens (>100 mg/kg/day in rodents) may induce mild hepatorenal stress. Clinical trials in osteoporosis demonstrate favorable safety profiles at therapeutic doses (15–60 mg/day), but long-term (>12 months) toxicity data in humans are lacking. Importantly, no IDD-focused studies have evaluated ICA's combinatory effects with NSAIDs or corticosteroids, which are commonly used in pain management. We emphasize these limitations to underscore the necessity for rigorous pharmacokinetic and toxicological investigations in future IDD research.

7. Conclusion

As a principal active component of Epimedium, ICA demonstrates multifaceted therapeutic potential for IDD through anti-inflammatory, antioxidative, and metabolic regulatory mechanisms. Current evidence indicates that ICA modulates the NF-κB pathway to rebalance cytokine production, activates antioxidant enzymes to counteract oxidative stress, and regulates bone/collagen metabolism through osteoblast/osteoclast activity. However, critical evaluation reveals three key limitations in existing research: (1) Discrepancies exist regarding ICA's dose-dependent effects, with some studies reporting U-shaped efficacy curves while others show linear relationships; (2) Most animal models fail to fully recapitulate human IDD pathophysiology, particularly in simulating chronic degeneration processes; (3) Reported bioavailability may not translate to clinical settings due to species-specific pharmacokinetics. These limitations underscore the need for standardized model systems and rigorous pharmacokinetic studies.

CRediT authorship contribution statement

LiLun Zhong: Writing – review & editing, Writing – original draft. ZhenWen Xu: Conceptualization. YingJun Peng: Methodology, Investigation. SongPeng Li: Methodology, Investigation. An Liu: Methodology, Investigation. ZhiDong Lin: Funding acquisition, Conceptualization.

Funding

This work was supported by the National Natural Science Foundation of China (82405186), the China Postdoctoral Science Foundation (2023M740777), The Guangdong Provincial Youth Innovation Talent Program for General Higher Education Institutions (2023KQNCX018), Traditional Chinese Medicine Research Project of the Guangdong Provincial Administration of Traditional Chinese Medicine (20244034). Special Research Project on Chinese Medicine Science and Technology, Guangdong Provincial Hospital of Chinese Medicine (YN2023QN06).

Declaration of competing interest

We would like to submit the enclosed manuscript entitled “Research progress on the mechanism of icariin in the treatment of intervertebral disc degeneration”, which we wish to be considered for publication. No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed.

Data availability

Data will be made available on request.