Effects and molecular mechanisms of Achyranthes bidentata Blume and Cyathula officinalis K.C. Kuan in the treatment of rheumatoid arthritis

Abstract

Achyranthes bidentata Blume (ABB; Chinese name: Huai Niuxi) and Cyathula officinalis K.C.Kuan (COK; Chinese name: Chuan Niuxi), two botanical drugs collectively termed “Niuxi” in traditional Chinese medicine (TCM), are widely used for rheumatoid arthritis (RA) management. This review comprehensively summarized the pharmacological mechanisms and therapeutic potential of the metabolites of ABB and COK on RA, while addressing limitations of current evidence. Of the 314 and 185 metabolites contained in ABB and COK, respectively, 22 metabolites (including Chikusetsusaponin V and chikusetsusaponin Ⅳa), showed multiple anti-RA activities. The mechanisms underlying the effects of ABB and COK with respect to the occurrence and development of RA (including inflammatory processes, immunoregulation, fibroblast-like synoviocytes, angiogenesis, oxidative stress, cartilage degradation, and bone destruction) were evaluated (Graphical Abstract). Numerous signaling pathways, such as the nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), are involved in RA. The metabolites contained in ABB and COK have significant medicinal value and potential in the treatment of RA, while in-depth mechanism studies and clinical research are warranted to support the clinical application of these metabolites.

1 Introduction

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by synovial inflammation, affecting approximately 1% of the population worldwide (van der Woude and van der Helm-van Mil, 2018). In the absence of treatment, RA can result in severe joint loss, deformity, and a high mortality rate (Babiker-Mohamed et al., 2024). Current treatments include non-steroidal anti-inflammatory drugs, glucocorticoids, disease-modifying antirheumatic drugs, and other immuno-modifiers (Baig et al., 2024). Although these drugs are effective against RA, approximately 40% of patients do not achieve clinical remission (Gao et al., 2024). Thus, there is an urgent need to development more efficacious anti-RA agents. Traditional Chinese medicine (TCM) has recently gained considerable attention due to the low cost, good safety profile, and multi-targeting nature of its medications (Wang et al., 2024a). TCM may be an important complementary medical strategy for RA.

“Niuxi” is one of the most commonly used medications in the TCM treatment of RA, with effects such as tonifying the liver and kidneys, strengthening muscles and bones, and relieving swelling and pain (Gao et al., 2013; Liu et al., 2013). Over 100 prescriptions for treating RA contain “Niuxi”, including Biqi capsule (Lv et al., 2023), Sanhan Chushi decoction (Ma et al., 2024), Qushi Zhitong Pills (Zhang et al., 2023). A meta-analysis of 15 studies involving 1,636 patients with RA showed that, compared with Western medicine, treatment with “Niuxi” and other TCMs, markedly increased the total effective rate and reduced the number of swollen joints, number of painful joints, rheumatoid factor (RF) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels (Lv et al., 2023). In a randomized controlled trial, compared to methotrexate and leflunomide, treatment with “Niuxi” and other TCMs combined with methotrexate and leflunomide in patients with RA obviously decreased CRP levels, ESR, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-17, RF, matrix metalloproteinase-3 (MMP-3) and transforming growth factor-β (TGF-β) (Chen et al., 2024). The National Medical Products Administration also approved numerous Chinese Patent Medicines containing “Niuxi” (e.g., Biqi capsules, Yuxuebi capsules, and Jishengshenqi pills) for the treatment of RA. A Bayesian network meta-analysis of 16 randomized controlled trials involving 10,213 patients with RA showed that Biqi capsules, Yuxuebi capsules, and glucosides of Tripterygium Wilfordii tablets were recommended for treating RA according to their clinical efficacy (Zhang et al., 2020a). Achyranthes bidentata Blume (ABB; Chinese name: Huai Niuxi) and Cyathula officinalis K.C.Kuan (COK; Chinese name: Chuan Niuxi) are both used as ‘Niuxi’. ABB and COK have been widely used to treat patients with RA in combination with other botanical drug, some of which are listed in Table 1.

COK, the root of C. officinalis Kuan, is traditionally thought to have anti-blood stasis (Cao et al., 2017), anti-inflammation (Yang et al., 2022), and hepatoprotective properties (Meng et al., 2019); in addition, it is used in the treatment of orthopedic diseases (Park et al., 2011). Huang et al. reported that COK impacts the hematologic, urogenital, and immune systems (Huang et al., 2019). The chemical metabolites contained in COK can be roughly divided into triterpenoid saponins, steroid ketones, polysaccharides, and others (Liang et al., 2022). Current pharmacologic studies of COK have primarily focused on cyasterone, achyranthan and polysaccharides (Han et al., 2015; Feng et al., 2019; Yang et al., 2022).

ABB, the dry root of A. bidentata (A.bidentata) and Achyranthes aspera Linn (A. aspera), prevents osteoporosis (Jiang et al., 2014b), exerts neurotrophic and neuroprotective effects (Wang et al., 2013), inhibits myocardial ischemic/reperfusion-induced injuries (Tie et al., 2013) and possesses antitumor properties (Zhong et al., 2020). A. aspera aqueous extract offers significant protection against arthritis and joint inflammation (Chinnasamy et al., 2019). Researchers have found that RA is related to excessive osteoclast resorption and defective osteoblast production (Yan et al., 2020). A. bidentata alcohol extract increases the proliferative capacity and stimulates the osteogenic differentiation of osteoblasts (Hua and Zhang, 2019). Moreover, it can inhibit osteoclast differentiation (Jiang et al., 2014b). ABB contains saponins, steroids, flavonoids, alkaloids, polysaccharides, and polypeptides. Of these metabolites, ecdysterone, polysaccharides, polypeptides, and saponins are the most characteristic metabolites of ABB (Jiang et al., 2014b).

Previous reviews have discussed the traditional uses, phytochemistry, and pharmacological properties of the genus Achyranthes (Li and Li, 1998; He et al., 2017). Further investigations included high-performance liquid chromatography analysis, processing, extraction conditions, and the biological activity of the saponin metabolites of Achyranthes root (Kiuchi, 2022). This review focuses on the pathogenesis of RA and the effects and molecular mechanisms of ABB and COK for the treatment of RA. A literature search was performed, focusing on research published up to May 2025. In detail, the metabolites contained in ABB and COK were examined using evidence available in the Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) (https://tcmspw.com/tcmsp.php) (Ru et al., 2014). Subsequently, the metabolites involved in RA were further filtered. The objective of this review was to improve our understanding of the anti-RA effects of ABB and COK. We first summarized the mechanisms underlying the effects of ABB and COK by focusing on the pathogenesis of the inflammatory process, immunoregulation, fibroblast-like synoviocytes (FLS), angiogenesis, oxidative stress, cartilage degradation, and bone destruction in RA. Data on the pharmacokinetic characteristics of the metabolites of ABB and COK were also summarized. This review attempts to comprehensively summarize the available information on the multiple beneficial effects of the metabolites of ABB and COK on RA, and provide scientific evidence for its traditional use.

2 Effects of ABB and COK on RA

2.1 Extract of ABB and COK

In an adjuvant-induced arthritis (AIA) rat model, treatment with a saponin-rich fraction of A. aspera (50 and 100 mg/kg) for 28 days markedly suppressed paw swelling, reduced the arthritic score, and improved the pain threshold (Kothavade et al., 2015). Zheng et al. isolated and identified ABB saponins in A. aspera root and explored their activity in rats with collagen-induced arthritis (CIA). ABB saponins (150 and 300 mg/kg) dramatically decreased the paw volume of arthritis rats. At the dose of 300 mg/kg, ABB saponins significantly suppressed soft tissue swelling and periarticular bone destruction and improved arthritis symptoms such as synovial joint space narrowing, synovial hyperplasia, fiber tissue hyperplasia, inflammatory cellular infiltration, cartilage erosion, and bony hyperplasia destruction (Zheng et al., 2016). In a rat AIA model, the total saponin content of ABB (30, 60, 120 mg/kg) significantly suppressed paw swelling and redness/inflammation severity in addition to improving synovial hyperplasia, and inflammatory cell infiltration (Fu et al., 2021).

Ecdysteroid-enriched fraction of COK could reduce the arthritis score, paw swelling, and improve histopathological deterioration, and suppress the levels of inflammatory factors, matrix metalloproteinases, and proteins expressed in rat synovial tissue (Huang et al., 2025).

2.2 Metabolites of ABB and COK

A total of 314 metabolites contained in ABB were searched in the literature and TCMSP database, including saponins, steroids, flavonoids, alkaloids, fatty acid, and lignan (Li et al., 2007b; Tao et al., 2019a; Teng et al., 2022; Wang et al., 2022a; Wang et al., 2022b; Yan et al., 2024). Moreover, 185 metabolites contained in COK were searched, including saponins, steroids, flavonoids, alkaloids, fatty acid, and lignan (Yan et al., 2024). Of those, 22 metabolites, mainly derived from the roots of ABB and COK, were related to the treatment of RA, comprising 7 terpenoids, 6 flavonoids, 3 steroids, 2 alkaloids, and 4 others (Table 2) (Chen et al., 2024b). Duan et al. reported that arthritis scores were markedly decreased by higenamine in CIA mice (Duan et al., 2016). Chikusetsusaponin Ⅳa decreased the arthritis index, paw thickness and number of swollen joints in CIA mice (Guo et al., 2021).

3 Mechanisms underlying the effects of ABB and COK on RA

3.1 Modulation of the inflammatory process

3.1.1 Effects on pro-inflammatory cytokines

It is well established that increased levels of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, as well as the imbalance of anti-inflammatory cytokines, such as TGF-β, IL-4, IL-10, and IL-13, lead to the development of RA (Cutolo et al., 2022).

TNF-α can induce the production of other inflammatory cytokines, attracting leukocytes and constructing a synovial inflammatory environment. The synovial inflammatory environment activates macrophages to produce additional pro-inflammatory cytokines, such as IL-6 and IL-1β, which increase synovial inflammation by recruiting and activating other innate immune cells (Kikyo, 2023). Moreover, pro-inflammatory cytokines initiate and maintain the production of further degradative enzymes and prostaglandins, promoting cartilage degradation, bone resorption, and osteoclastogenesis (Markovics et al., 2021). In addition, IL-17 activates multiple downstream signaling cascades that increase the levels of several inflammatory cytokines and chemokines (Adamopoulos et al., 2010). Furthermore, IL-17 enhances osteoblast-mediated bone resorption by promoting the activity of receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), and prostaglandin E2 (PGE2), thereby increasing cathepsin K (CTSK) and MMP expression (Zhang F. et al., 2011; Ganesan and Rasool, 2017).

In vivo studies showed that 20-hydroxyecdysone (Sun et al., 2017), stigmasterol (Khan et al., 2020), azelaic acid (Sial et al., 2024), ursolic acid (Baek et al., 2014), higenamine (Duan et al., 2016), cichoric acid (Jiang et al., 2014a), p-Coumaric acid (Neog et al., 2017), maslinic acid (Shimazu et al., 2019), rhoifolin (Peng et al., 2020), nobiletin (Yang et al., 2017), kaempferitrin (Wang and Zhao, 2019), and kaempferol (Aa et al., 2020) reduced the production of IL-6, IL-1β, TNF-α, IL-21 and IL-17 (Table 2).

Mechanistically, the primary signaling pathways involved in RA include Janus kinase (JAK), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and nuclear factor kappa-B (NF-κB) (Ding et al., 2023). Chikusetsusaponin IVa (Wang et al., 2015), chikusetsusaponin V (Wang et al., 2014), momordin Ic (Zheng et al., 2020), 20-hydroxyecdysone (Sun et al., 2017), stigmasterol (Khan et al., 2020), wogonin (Yang et al., 2024), caffeic acid (Wang et al., 2017), cichoric acid (Jiang et al., 2014a), p-Coumaric acid (Neog et al., 2017), rhoifolin (Peng et al., 2020), nobiletin (Yang et al., 2017), kaempferitrin (Wang and Zhao, 2019), hyperoside (Jin et al., 2016) suppressed the secretion of IL-1β, IL-6, IL-8, IL-17, and TNF-α via inhibiting NF-κB activation (Figure 1). Chikusetsusaponin IVa (Wang et al., 2015; Xu et al., 2021), chikusetsusaponin V (Xu et al., 2022), stigmasterol (Khan et al., 2020), caffeic acid (Wang et al., 2017), p-Coumaric acid (Neog et al., 2017), nobiletin (Yang et al., 2017) inhibited the production of pro-inflammatory cytokines by down-regulating the MAPK pathway (Figure 1). Moreover, wogonin and higenamine decreased the expression of TNF-α, IL-1β, and IL-6 via the PI3K/protein kinase B (PI3K/AKT) pathway (Duan et al., 2016; Yang et al., 2024). Chikusetsusaponin IVa could effectively and stably bind to IL-1β and interferon-gamma (IFN-γ) and inhibit the JAK/STAT signaling pathway (Guo et al., 2021) (Figure 1).

FIGURE 1

3.1.2 Effects on anti-inflammatory cytokines

IL-10 can downregulate the expression of IL-1β, IL-6 and TNF-α, and reduce osteoclast formation by directly acting on osteoclast precursors (Kitaura et al., 2020). It was previously reported that β-sitosterol, azelaic acid, wogonin, and stigmasterol increased the expression of IL-10 (Liu et al., 2019; Khan et al., 2020; Sial et al., 2024; Yang et al., 2024). The mechanisms underlying these effects may be related to suppression of the MAPK, NF-κB, and PI3K/AKT pathways (Khan et al., 2020; Yang et al., 2024).

IL-4 exerted anti-inflammatory, anti-angiogenic, and bone-protective effects via suppressing pro-inflammatory cytokines, vascular endothelial growth factor (VEGF), osteoclast activation, and bone-resorbing cytokines (Iwaszko et al., 2021). In addition, production of IL-4 was increased by azelaic acid (Sial et al., 2024) (Table 2).

3.1.3 Effects on nitric oxide (NO) and inducible nitric oxide synthase (iNOS)

NO is a significant inflammatory mediator overproduced in serum and synovial fluid of patients with RA, showing a significant correlation with disease activity (Farrell et al., 1992; Ali et al., 2014). Diverse cytokines including TNF-α and IL-6 increased the secretion of iNOS, subsequently promoting the production of NO by a broad spectrum of cells (e.g., macrophages, neutrophils, osteoclasts, osteoblasts, and FLS) into inflamed joints (Spiller et al., 2019; Huang et al., 2023). NO increased the production of inflammatory mediators via regulating the toll-like receptor 4/NF-κB (TLR4/NF-κB) pathway (Huang et al., 2023). Moreover, NO promoted the imbalance of T helper 17/regulatory T (Th17/Treg) cells, Th1/Th2 cells, and bone resorption/formation (Nagy et al., 2010; Spiller et al., 2019; Huang et al., 2023).

Chikusetsusaponin IVa (Wang et al., 2015; Xin et al., 2020), chikusetsusaponin V (Wang et al., 2014), momordin Ib (Huang et al., 2021), 20-hydroxyecdysone (Sun et al., 2017), β-Sitosterol (Liu et al., 2019), stigmasterol (Khan et al., 2020), ursolic acid (Baek et al., 2014), cichoric acid (Jiang L. et al., 2014), p-Coumaric acid (Neog et al., 2017), maslinic acid (Shimazu et al., 2019), nobiletin (Yang et al., 2017), and kaempferol (Aa et al., 2020) decreased the expression of iNOS and NO (Table 2).

3.1.4 Effects on PGE2 and cyclooxygenase-2 (COX-2)

Apart from the above mechanisms, PGE2 formed by COX is a key inflammatory mediator in RA (Park et al., 2006). The production of PGE2 and COX-2 was increased by pro-inflammatory cytokines (e.g., TNF-α and IL-1β) and decreased by anti-inflammatory cytokines (e.g., IL-4, IL-10, and IL-13) (Martel-Pelletier et al., 2003). Evidence has shown that PGE2 is related to inflammation, angiogenesis and bone destruction by increasing the expression of IL-6 (Inoue et al., 2002), VEGF (Ben-Av et al., 1995), and MMP-1 (Kunisch et al., 2009).

Chikusetsusaponin IVa (Wang et al., 2015), chikusetsusaponin V (Kim et al., 2015), momordin Ic (Yoo et al., 2017), stigmasterol (Khan et al., 2020), azelaic acid (Sial et al., 2024), caffeic acid (Wang et al., 2017), cichoric acid (Jiang et al., 2014a), p-Coumaric acid (Neog et al., 2017), maslinic acid (Shimazu et al., 2019), nobiletin (Yang et al., 2017), kaempferol (Aa et al., 2020), and 20-Hydroxyecdysone (Yoo et al., 2017) suppressed the production of COX-2 and PGE2 (Table 2).

3.2 Regulation of immunity

3.2.1 Effects on T cells

Through the induction of diverse cytokines, CD4⁺ T cells differentiate towards T cell subsets, including Th17, Treg, Th1, and Th2 (Gomez-Bris et al., 2023). Studies demonstrated that the imbalance of Th17/Treg and Th1/Th2 cells was closely related to inflammation and bone destruction in RA (Wang et al., 2024b; Yang and Zhu, 2024). Ursolic acid and kaempferol regulated the balance of Treg and Th17 cells by decreasing Th17 cells and increasing Treg cells (Baek et al., 2014; Lin et al., 2015; Lee et al., 2018). Ursolic acid decreased the cytokines of Th1 cells (Ahmad et al., 2006). Of note, ursolic acid increased the cytokines of Th2 cells (Ahmad et al., 2006) (Table 2).

3.2.2 Effects on B cells

The functions of B cells include antigen presentation, cytokine secretion and autoantibody production, which are closely associated with the pathogenesis of RA (Wu et al., 2021a; Jang et al., 2022). In vitro studies showed that ursolic acid suppressed B cell activation and differentiation (Baek et al., 2014). Aa et al. reported that kaempferol decreased anti-collagen type II IgG levels in CIA mice (Aa et al., 2020). Liu et al. reported that β-sitosterol suppressed the levels of IgG and IgG1 antibodies, but did not affect those of IgG2c (Liu et al., 2019) (Table 2).

3.2.3 Effects on macrophages

Macrophages play a crucial role in RA pathogenesis via polarization into M1 and M2 types (Yang et al., 2020). M1 macrophages produce pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, IL-8, IL-12, and IL-23), while M2 macrophages produce anti-inflammatory cytokines (e.g., IL-10, IL-4, IL-13, and TGF-β) (Zheng et al., 2024). The proportions of M1 and M2 macrophages are imbalanced in the synovial fluid (Zhu et al., 2015), synovium (Ambarus et al., 2012) and peripheral blood (Tardito et al., 2019) in patients with RA. By modulating macrophage polarization, β-sitosterol inhibited the expression of iNOS, IL-1β, CD86, and major histocompatibility complex class II (MHCII), whereas it increased that of arginase-1 (ARG1), IL-10, CD163, and CD206 (Liu et al., 2019) (Table 2).

3.3 Effects on FLS

Proliferation of synovial tissue, an important feature of RA, is mainly attributed to hyperproliferation and decreased apoptosis of FLS (Tu et al., 2018). Coptisine (Xu et al., 2024), wogonin (Yang et al., 2024), kaempferitrin (Wang and Zhao, 2019), hyperoside (Jin et al., 2016), and kaempferol (Lee et al., 2018; Pan et al., 2018) suppressed the proliferation, migration, and invasion of FLS. Furthermore, caffeic acid (Wang et al., 2017), ursolic acid (Kim et al., 2018), and kaempferitrin (Wang and Zhao, 2019) induced apoptosis of FLS.

FLS have pro-inflammatory, angiogenic, and bone-destructive effects via overproduction of pro-inflammatory cytokines, chemokines, pro-angiogenic factors, collagenases, aggrecanases, cathepsins, and RANKL (Nygaard and Firestein, 2020; Wu et al., 2021b). It was reported that wogonin (Yang et al., 2024), caffeic acid (Wang et al., 2017), and hyperoside (Jin et al., 2016) suppressed the expression of TNF-α, IL-1β, IL-6, IL-8, IL-17 and IL-18 produced by FLS (Table 2).

3.4 Inhibition of angiogenesis

In RA, angiogenesis can be induced by inflammation, immune imbalance, and hypoxia, promoting synovial hyperplasia, pannus formation, and bone destruction (Wang et al., 2021). Angiogenesis is tightly regulated by VEGF and its receptors, which have been extensively studied (Khodadust et al., 2022). β-sitosterol and wogonin suppressed rheumatoid synovial angiogenesis via down-regulating vascular endothelial growth factor receptor 2 (VEGFR2) and phospho-VEGFR2 expression (Lin et al., 2006; Qian et al., 2021).

3.5 Inhibition of oxidative stress

In the arthritic joint, neutrophils can drive inflammation by releasing a variety of potentially harmful peptides, enzymes, and toxic oxygen metabolites (Cecchi et al., 2018). Myeloperoxidase, an abundant peroxidase in neutrophils, is found in the plasma and synovium of patients with RA (Fernandes et al., 2012; Odobasic et al., 2014). Moreover, increased oxidative stress decreases the levels of superoxide dismutase, catalase, glutathione, glutathione S-transferase, glutathione reductase, and glutathione peroxidase (Tang et al., 2022). The decrease in antioxidant defense is accompanied by a concurrent increase in the levels of ROS and NO (Wójcik et al., 2021). High levels of malondialdehyde indicate increased lipid peroxidation, which can activate signaling pathways involved in the inflammatory processes of RA (Tsikas and Mikuteit, 2022). Azelaic acid (Sial et al., 2024), 20-hydroxyecdysone (Sun et al., 2017), higenamine (Duan et al., 2016), and rhoifolin (Peng et al., 2020) can inhibit the decrease in superoxide dismutase, catalase, glutathione, glutathione peroxidase activity, and the increase in malondialdehyde content (Table 2).

3.6 Inhibition of cartilage and bone destruction

Under normal physiologic circumstances, bone remodeling is continuously conducted by osteoblasts and osteoclasts, which are responsible for bone resorption and bone formation, respectively. However, under arthritic conditions, the excessive activation of osteoclasts is associated with suppressed osteoblast development.

3.6.1 Effects on osteoclasts

In RA, osteoclasts play a crucial role in bone resorption. Osteoclasts are formed by the fusion of osteoclast precursors, derived from monocyte/macrophage precursors or hematopoietic stem cells. TNF-α can regulate bone resorption by increasing RANKL and M-CSF expression in osteoblasts and stromal cells (Marahleh et al., 2019). The binding of M-CSF and colony-stimulating factor 1 receptor is essential for the survival, proliferation, differentiation and function of myeloid cells, including osteoclasts and monocytes/macrophages (Mun et al., 2020). Inhibition of osteoclastogenesis, osteoclast differentiation, and osteoclast function is a major target in the treatment of RA. Chikusetsusaponin IVa, momordin Ib and momordin IIa inhibited the formation of 1α,25(OH)₂D₃-induced osteoclast-like multinucleated cells in a co-culture system without irreversible toxicity (Li et al., 2005). Stigmasterol inhibited the expression of osteoclast-specific genes including cathepsin K, MMP-9 and tartrate-resistant acid phosphatase (TRAP) (Xie et al., 2023) (Table 2).

Upregulation of osteoclast activity in the development of RA is controlled by osteocytes through the osteoprotegerin/RANKL/RANK (OPG/RANKL/RANK) system (Zhang and Wen, 2021). RANKL binds to RANK on mononuclear osteoclast precursors. Subsequently, it recruits TRAF6, TGF-β activated kinase 1 binding protein 1 (TAB1), and TAB2 to sequentially activate TAK1 and promotes the activation of MAPKs, NF-κB and c-Fos. Finally, it induces the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is a crucial transcription factor of osteoclast differentiation (Maeda et al., 2022; Yang and Zhu, 2024). OPG, a decoy receptor of RANKL, blocks the RANKL-RANK interaction to inhibit osteoclast formation (Yao et al., 2021). Oleanolic acid significantly suppressed osteoclast differentiation and bone resorption via the estrogen receptor alpha/miR-503/RANK (ERα/miR-503/RANK) signaling pathway (Xie et al., 2019). Caffeic acid exerted an inhibitory effect on osteoclastogenesis by inhibiting the expression of NFATc1 (Tang et al., 2006). p-Coumaric acid inhibited osteoclastogenesis via up-regulating OPG expression and down-regulating RANKL, NFATc1 and c-Fos expression (Neog et al., 2017). Additionally, kaempferol attenuated osteoclast differentiation by suppressing the MAPK/c-fos/NFATc1 signaling pathway (Lee et al., 2014) (Table 2).

3.6.2 Effects on osteoblasts

Osteoblasts are derived from mesenchymal stem cells in the bone marrow. These cells differentiate into osteoblasts, adipocytes or chondrocytes. Their differentiation into the osteogenic lineages is tightly controlled by molecular factors, such as bone morphogenic protein (BMP) and Wnt pathways (Datta et al., 2008; Zhang et al., 2011b). The canonical Wnt signalling pathway affects osteoblast proliferation and differentiation. MAPK is also thought to mediate the activation of several gene products related to bone formation, such as alkaline phosphatase (ALP) and transcription factors, including runt-related transcription factor 2 (RUNX2), osterix (OSX), and BMP2 (Hua and Zhang, 2019). Numerous reports over the last 2 decades showed that osteoblast differentiation also relies on miRNAs, and several miRNAs target the Wnt and BMP pathways, thereby modulating osteoblast differentiation (Ponzetti and Rucci, 2021). ALP activity is the gold standard for evaluating osteoblast differentiation. Chikusetsusaponin IVa was positively correlated with ALP activation, while chikusetsusaponin V and chikusetsusaponin IV were negatively correlated with ALP (Tao et al., 2019a). Nobiletin augmented the expression of type I collagen (COL-I), ALP, osteocalcin (OCN), and collagen type I alpha 1 chain (COL1A1) via promoting the BMP2/RUNX2 pathway (Pang et al., 2021) (Table 2).

3.6.3 Effects on MMPs

RA is characterized by the loss of cartilage and bone matrix integrity (Komatsu and Takayanagi, 2022). Reversing the anabolic/catabolic imbalance of matrix remodeling is crucial to maintaining cartilage and bone integrity (Deng et al., 2022). Extracellular matrix (ECM) destruction occurs in the RA joint. The ECM primarily consists of type II collagen and proteoglycans. Matrix-degrading enzymes, such as MMPs and the A disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) family degrade the ECM (Bian et al., 2023). ECM breakdown products (e.g., such as fibronectin fragments, tenascin C, and hyaluronic acid) can induce the production of pro-inflammatory cytokines, as well as MMP-3, MMP-9, and MMP-13, accelerating the breakdown of cartilage and bone. Inflammation can also promote the expression of MMPs, ADAMTS, and ROS, further promoting cartilage and bone destruction. Nobiletin (Imada et al., 2008; Liu et al., 2020), kaempferitrin (Wang and Zhao, 2019), and kaempferol (Yoon et al., 2013; Pan et al., 2018) significantly suppressed the expression of MMPs and ADAMTS family (Table 2).

4 Pharmacokinetic characteristics

Currently, there is limited number of pharmacokinetic studies of ABB extracts. Tao et al. studied the pharmacokinetics of chikusetsusaponin IV, chikusetsusaponin IVa and ginsenoside Ro in rats after oral administration of crude and salt-processed ABB. A double-peak phenomenon was observed for these three saponins. After oral gavage of crude and salt-processed ABB in rats, the highest values of the area under the curve up to the last quantifiable time-point (AUC_0-t) and maximum concentration (C_max) of the three saponins were observed in kidney tissue, followed by liver, spleen, heart, and lung tissues. The concentration of ginsenoside Ro and chikusetsusaponin IVa was higher in the raw extract than the salt-processed ABB. However, the C_max values of ginsenoside Ro and chikusetsusaponin IVa in rat plasma were lower in the raw group than the salt-processed group. This finding demonstrated that salt-processing resulted in enhanced bioavailability (Tao et al., 2018; Tao et al., 2019b).

Cyasterone, 25-epi-28-epi-cyasterone, precyasterone and capitasterone from COK phytoecdysteroids extract in normal and AIA rats were studied and the results demonstrated that the plasma concentrations of those metabolites were lower in AIA rats than in normal rats at almost all time points. The mechanism of the difference between normal rats and AIA rats with RA requires further research (Wang et al., 2023).

5 Safety assessment of ABB and COK

ABB is a botanical drug, commonly used to treat a variety of diseases. The oral toxicity and genotoxicity of single-dose (500, 1000, and 2000 mg/kg) and 4-week repeated-doses of water extract of ABB were evaluated. The single-dose oral toxicity study showed no mortality or treatment-related body weight changes, with the lethal dose in rats estimated to exceed 2000 mg/kg. The 4-week study on repeated oral doses showed that ARB did not lead to significant changes in body weight, organ weight, food intake, or hematological and serum biochemical parameters across all groups. Meanwhile, ABB did not induce genotoxicity in the chromosomal aberration test and micronucleus test (Hyun et al., 2021).

The mice displayed neurotoxic and gastrointestinal toxic effects after receiving a high dose of water extract of COK. The range of maximum tolerance doses for samples from different origins was between 34.9 and 56.8 g/kg (Huang et al., 2019). The recommended dosage for COK is 5–10 g in the National Medical Products Administration. Therefore, it is crucial to avoid high doses or prolonged use in clinical practice.

6 Discussion

RA is an inflammatory autoimmune disease. Currently drugs not only alleviate pain and swelling but also prevent damage to joint. Despite this, treating up to 20% of RA patients is challenging (de Hair et al., 2018), and these drugs can result in gastrointestinal bleeding and liver toxicity (Lin et al., 2020). TCM is gradually developing into an important complementary medical treatment strategy. ‘Niuxi’ is one of the most commonly utilized TCM treatment options for RA (Cai et al., 2024). Studies have shown that the metabolites contained in ABB and COK can significantly delay the progression of RA. However, some anti-RA effects of these metabolites have mostly remained at the in vitro level, further investigation is necessary to assess the therapeutic impact of metabolites contained in ABB and COK for the treatment of RA.

This review revealed that 22 metabolites contained in ABB and COK, including higenamine and chikusetsusaponin Ⅳa, exhibited anti-RA activity. These metabolites modulate the inflammatory process, regulate immunity, decrease the proliferation, migration, and invasion of FLS, induce apoptosis of FLS, inhibit angiogenesis and oxidative stress, and suppress the destruction of cartilage and bone. Many signaling pathways, such as NF-κB, MAPK, PI3K/AKT, and JAK/STAT, participate in the progression of RA (Table 2; Figure 1). NF-κB, MAPK, PI3K/AKT are important intracellular signaling pathways that play critical roles in the inflammation and bone destruction of RA (Liu et al., 2021a). TNF-α binds to TNFR and RANKL binds to RANK, recruiting TRAF and activating the PI3K/AKT, NF-κB and MAPK pathway (Ma et al., 2018; Shi and Sun, 2018). However, the research on its mechanism is still not in-depth. In the future, genomics, proteomics, and metabolomics and network pharmacology can be used to clarify the mechanism of ABB and COK for the treatment of RA, thereby enhancing its benefits to human health (Zhang et al., 2024; Lu, 2025). Meanwhile, the use of standardized animal models for RA, together with TCM symptom characteristics, is crucial for studying the molecular mechanisms of ABB and COK on RA (Zhou et al., 2023).

The present review indicates that the metabolites contained in ABB and COK may be a great complementary medicine option for RA. Although the mechanisms of metabolites contained in ABB and COK for treating RA were summarized via multiple targets and pathways, there is limited number of studies to explore combination therapy of metabolites from ABB or COK. It is necessary to explore combination therapy of metabolites from ABB or COK on RA in the future.

Chinese medicinal materials from animals, plants, and minerals must be treated properly before being used in decoctions. Such processes greatly influence the content and pharmacological activity of major metabolites (Han et al., 2019; Chen et al., 2020). ABB is generally prepared with yellow rice wine or salt water to enhance actions, such as enriching the kidneys, nourishing the liver, and strengthening the sinews and bones. Salt-processing leads to high levels of β-ecdysterone, 25-S inokosterone, 25-R inokosterone, chikusetsusaponin V, and chikusetsusaponin IVa, which were higher than that those detected in raw and wine-processed ABB (Yang et al., 2018). The levels of ginsenoside Ro and chikusetsusaponin IV were reduced, which could enhance the anti-osteoporotic effects of ABB (Tao et al., 2019a). The processing method has a significant influence on the content of each metabolite.

Previous studies have reported that the plasma concentrations of COK-derived phytoecdysteroids were lower in AIA rats than in normal rats (Wang et al., 2023). Various pathological mechanisms of RA may lead to changes in the absorption of metabolites, which requires further research.

In conclusion, ABB and COK metabolites represent have significant medicinal value and potential in the treatment of RA. Thus far, studies on the anti-RA activity of these metabolites have mostly remained at the in vitro level, and mechanism research is not in-depth enough, clinical research evidence is lacking. Therefore, in-depth mechanism studies and clinical research are warranted to support the clinical application of these metabolites.

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