NF-κB is a transcription factor composed of Rel family proteins (such as p65 and p50), which usually binds to IκB and exists in an inactive form in the cytoplasm (Zhang et al., 2017). Upon endogenous stimulation, IκB kinase (IKK) is activated, leading to the phosphorylation and degradation of IκB, which releases NF-κB to translocate into the nucleus and regulate the transcription of downstream genes, including pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and adhesion molecules, thereby participating in diverse biological processes such as inflammation, immune responses, cell proliferation, apoptosis, and differentiation (Guo et al., 2024). In RA, activation of this pathway promotes the expression of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, strongly induces M1 polarization, and exacerbates synovial inflammation and joint destruction (Marques et al., 2025).

Triptolide, an extract derived from the botanical drug Tripterygium wilfordii Hook. f., not only inhibits the binding of NF-κB to DNA but also cooperatively suppresses the MAPK and STAT1 pathways, thereby reducing proinflammatory cytokine secretion, blocking M1 polarization, and exerting anti-inflammatory, antiproliferative, and immunosuppressive effects. Preclinical studies have demonstrated that Triptolide can significantly reduce arthritis scores and attenuate bone erosion in animal models (Yang et al., 2016; Wang X. et al., 2025). Clinical observations further suggest that formulations derived from these metabolites, such as Tripterygium glycoside tablets, may provide symptomatic relief in RA patients. However, their therapeutic efficacy and safety remain to be substantiated by larger, high-quality clinical trials. Particular attention should be given to their potential hepatotoxicity and nephrotoxicity, highlighting the need for rigorous safety monitoring in clinical application (Zhang Y. et al., 2021; Zhou et al., 2025). Glaucocalyxin B (Gla B), a sesquiterpene extracted from Isodon japonicus var. glaucocalyx, has been proven in experiments to suppress NF-κB signaling via direct targeting of p65, significantly lowering TNF-α and IL-1β levels without altering IL-10 or TGF-β1 expression. In models of joint inflammation, it exhibits strong protective effects on cartilage (Han et al., 2021). Punicalagin, a bioactive substance isolated from Punica granatum L., has been shown in CIA models to suppress NF-κB pathway receptor activators, mitigate M1 macrophage polarization and pyroptosis, and markedly relieve joint pathological inflammation (Ge et al., 2022). Importantly, despite their promising effects in preclinical studies, challenges including poor oral bioavailability and rapid metabolic clearance limit their clinical application, highlighting the urgent need for formulation optimization, such as nanocarrier-based delivery systems.

The JAK-STAT signaling pathway is a major route for cytokine signal transduction, comprising the JAK family (including JAK1, JAK2, TYK2, and JAK3) and the STAT family (including STAT1, STAT3, STAT4, STAT5a/b), and is broadly involved in regulating immune responses, inflammatory reactions, and various biological processes such as cell proliferation, differentiation, and apoptosis (Samra et al., 2025). In RA, aberrant activation of the JAK-STAT pathway leads to elevated levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, exacerbating synovial inflammation and bone destruction, and by regulating osteoblast and chondrocyte functions, promotes bone resorption and cartilage degradation, aggravating joint damage (Hu et al., 2022). It has also been reported that phosphorylation of STAT1 and STAT3 promotes M1 macrophage polarization, with IFN-γ inducing the M1 phenotype through the JAK-STAT1 axis (Fortelny et al., 2024). In addition, through involvement in pain transmission and Th17 cell differentiation, it is intimately linked to chronic pain and bone destruction in RA (Simon et al., 2021).

Resveratrol, a naturally occurring polyphenol, exhibits anti-inflammatory effects; studies have demonstrated that it inhibits M1 polarization by downregulating the JAK1-STAT1/STAT3 pathway and deacetylating NF-κB p65, thereby reducing the secretion of proinflammatory mediators including IL-6 and IL-12, ultimately relieving synovitis in animal models (Oliveira et al., 2017; Wang P. et al., 2024). Jolkinolide B (JB), a diterpene metabolites isolated from Euphorbia pekinensis Rupr., in plant, exhibits anticancer, anti-inflammatory, and antituberculosis properties. Research has demonstrated that JB markedly decreases arthritis scores and synovial hyperplasia in CIA rats by inhibiting the JAK2/STAT3 signaling pathway and reducing inflammatory cytokine levels. It efficiently antagonizes M1 polarization, thereby alleviating inflammation and preventing bone erosion in CIA models (Yan et al., 2024). The mechanism involves JB suppressing mRNA expression of inflammatory cytokines in the ankle joints of CIA rats and reducing their levels in LPS-stimulated RAW264.7 macrophages, effectively inhibiting M1 polarization and significantly downregulating JAK2/STAT3 protein expression. Sappanone A (SA), an active plant metabolites of Tamarindus indica L., possesses anti-inflammatory, antioxidant, and bone-protective properties. Research has shown that SA can downregulate the protein phosphorylation levels of JAK2, STAT3, PI3K, AKT, and p65 in vivo and in vitro, and reverse the increase in protein phosphorylation levels of PI3K/AKT/NF-κB and JAK2/STAT3 pathway-related proteins induced by agonists, thereby reducing the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-17. While promoting the levels of the anti-inflammatory cytokine IL-10, inhibiting M1 polarization while promoting M2 polarization, thereby significantly reducing the arthritis index in CIA rats, alleviating paw swelling, and improving inflammatory cell infiltration and cartilage degradation (Deng et al., 2024). Nevertheless, these conclusions largely stem from in vitro and animal experiments, with the mechanisms of action yet to be fully elucidated. Their clinical translation and real-world efficacy in humans demand further confirmation in rigorous randomized controlled trials. While JAK-STAT inhibitors are already in clinical use, metabolites from plants, with their multi-target characteristics, may provide superior safety. Further attention should be directed toward their potential synergy with current therapies and their long-term safety profile.

The MAPK signaling pathway is also one of the key intracellular signal transduction cascades. Studies have shown that aberrant activation of the MAPK pathway can enhance the expression of M1-associated genes (such as iNOS and COX-2), leading to abnormal proliferation of synovial cells and MMP-mediated joint structural damage (Paunovic and Harnett, 2013; Baumann et al., 2021).

The principal plant metabolite of Andrographis paniculata, andrographolide (AD), suppresses NF-κB and MAPK signaling, inhibits IκBα degradation, diminishes ROS generation, decreases IL-6 and IL-1β levels, and regulates innate and adaptive immunity, suggesting promising therapeutic potential in RA (Zeng et al., 2022; Chen et al., 2025). Curcumin, extracted from the rhizome of Curcuma longa, is a natural plant metabolite known for its anti-inflammatory and immunoregulatory properties. Research has shown that curcumin can inhibit TLR4/NF-κB, MAPK, and NLRP3 inflammasome, suppress IKKβ activity, downregulate miR-155, reduce M1 markers such as iNOS and COX-2, and simultaneously activate Nrf2 to inhibit ROS accumulation, induce M2 phenotype polarization, exert anti-inflammatory and antioxidant activities, and effectively alleviate synovial inflammation and cartilage and bone destruction in RA (Mohammadian Haftcheshmeh and Momtazi-Borojeni, 2020; Wang and He, 2022). Nevertheless, existing research suggests that curcumin suffers from poor bioavailability and complex metabolic processing in the body. Oxypeucedanin hydrate (OXH) is a naturally occurring coumarin with notable biological activity. Liu et al. (2024) found that OXH can inhibit the NF-κB/MAPK pathways, reduce the release of proinflammatory cytokines and ROS production, and significantly improve symptoms and bone erosion in CIA models. However, its clinical efficacy still needs to be confirmed through high-quality randomized controlled trials in humans. MAPK signaling exhibits extensive cross-talk with pathways such as NF-κB and JAK-STAT. The multi-target nature of plant metabolite may potentiate anti-inflammatory responses by concurrently regulating several intersecting nodes, but the exact mechanisms of synergy remain to be elucidated.

TLRs, a type of pattern recognition receptor, detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to trigger downstream signaling pathways including NF-κB and MAPK, thereby broadly participating in inflammatory responses and immune modulation (Fitzgerald and Kagan, 2020). In RA patients, TLR expression is significantly upregulated in synovial tissue, particularly TLR2, TLR3, TLR4, and TLR7. These receptors recognize plant metabolites or tissue damage products, activating inflammatory signaling pathways, ultimately leading to excessive synoviocyte proliferation, cytokine release, and bone erosion, and representing one of the initiating events of RA inflammation (Thwaites et al., 2014).

Ginsenoside Rb1, the main active plant metabolite of Panax ginseng, exhibits significant anti-inflammatory activity. Experiments have shown that Rb1 reduces the release of inflammatory cytokines and iNOS expression via the TLR4-MyD88-NF-κB/MAPK pathway. In CIA models, mice treated with Rb1 showed markedly decreased TLR4 and MyD88 protein expression in joint tissues, accompanied by alleviated synovial inflammation and improved cartilage damage (Gao et al., 2020; Li W. et al., 2025). Euphorbia factor L2 (EFL2), a diterpenoid plant metabolite derived from Euphorbia seeds, has been shown by Tang et al. (2021) in animal studies to specifically target the TLR7 signaling pathway, inhibit IRAK4 autophosphorylation and its interaction with IRF5, block IRF5 nuclear translocation and type I interferon production, suppress TLR7-mediated NF-κB activation, reduce M1 macrophage marker expression, and significantly improve arthritis scores and pathological changes in STA mouse models. These findings offer guidance for the prospective clinical use of this plant metabolites. As upstream targets of inflammation, inhibition of TLRs can block the inflammatory cascade at its source; however, due to functional redundancy among TLR family members, the receptor selectivity of plant metabolite needs to be further clarified.

The NLRP3 inflammasome is a key multiprotein complex widely involved in immune responses and inflammatory regulation. It activates downstream caspase-1 by sensing various danger signals inside and outside cells (such as pathogen-associated molecular patterns, damage-associated molecular patterns, urate crystals, etc.), which in turn promotes the maturation and release of pro-inflammatory cytokines IL-1β and IL-18 (Li et al., 2024), These inflammatory factors further activate effector T cells and M1 macrophages, triggering local and systemic inflammatory responses and exacerbating immune attacks on the joints.

In light of the pivotal role of the NLRP3 inflammasome in the pathology of RA and its status as an inflammatory amplifier, targeting its assembly or activation has become a key strategy in the development of new therapeutic approaches for RA. For example, Baicalin—a flavonoid derived from Scutellaria baicalensis—reverses the TLR-2-NF-κB-mediated activation of the NLRP3 inflammasome pathway, inhibits inflammasome assembly, blocks Caspase-1 activation, reduces IL-1β production, and suppresses M1 polarization, thereby exerting antioxidant and anti-inflammatory effects (Hang et al., 2018; Ishfaq et al., 2021). Loganin, a cyclopentanoid monoterpene glycoside derived from Cornus officinalis, has been demonstrated in preclinical studies to block NF-κB signaling, attenuate NLRP3 inflammasome activation, inhibit M1 macrophage polarization, and mitigate experimental arthritis through its anti-inflammatory properties (Li et al., 2021; Zhang J. et al., 2021). It is evident that the NLRP3–NF-κB positive feedback loop plays a key role in amplifying inflammation, and the concurrent suppression of these two pathways by plant metabolites may exert synergistic anti-inflammatory benefits. With further validation of clinical efficacy, these plant metabolite may hold promising therapeutic potential in the treatment of RA.

Nrf2 (Nuclear Factor Erythroid 2-related Factor 2) is a central transcription factor in the antioxidant response, primarily regulating the expression of downstream antioxidant enzymes and anti-inflammatory proteins by binding to the antioxidant response element (ARE). Examples include heme oxygenase-1 (HO-1), which is a key anti-inflammatory protein that catalyzes the degradation of heme into carbon monoxide (CO), iron ions, and biliverdin, thereby exerting antioxidant and anti-inflammatory effects (Sha et al., 2023). Consequently, the Nrf2/HO-1 signaling pathway is crucial for preserving cellular redox homeostasis, suppressing inflammation, and shielding tissues from oxidative stress-related injury (O'Rourke et al., 2024). In RA, oxidative stress levels are significantly elevated, causing cellular and tissue damage. Activation of Nrf2 can upregulate HO-1, reduce ROS, inhibit the release of inflammatory mediators, and alleviate joint damage (Hung et al., 2024). Additionally, Nrf2/HO-1 pathway activation reduces oxidative stress, inhibits M1 macrophage polarization, and facilitates M2 polarization, with these effects partly achieved via modulation of the TGF-β/SMAD, TLR/NF-κB, and JAK/STAT signaling pathways (Kobayashi et al., 2016).

Asiatic acid (AA), the main active metabolite of the Centella asiatica, inhibits the proliferation and colony formation of RA fibroblast-like synoviocytes by activating the Nrf2/HO-1/NF-κB signaling pathway (Zhang L. et al., 2024). Sinomenine (SIN), a metabolite isolated from the botanical drug Sinomenium acutum, exhibits anti-inflammatory properties. Guo et al. (2025) and colleagues showed in animal experiments that SIN activates the Nrf2/HO-1 signaling pathway and inhibits NF-κB signaling in mouse chondrocytes, reducing IL-1β-induced inflammatory responses and cartilage degradation, which ameliorates cartilage damage in collagen-induced arthritis (CIA) mouse models, highlighting SIN’s potential new application in RA therapy. Magnoflorin (MAG), the principal plant metabolite from Cornus officinalis, has anti-inflammatory, antioxidant, and immunosuppressive activities. Shen et al. (2022) revealed that MAG partly inhibits the PI3K/Akt/NF-κB signaling axis and activates the Keap1-Nrf2/HO-1 pathway, markedly decreasing inflammatory cytokines including iNOS, COX-2, IL-6, and IL-8. This leads to effective suppression of M1 macrophage polarization and promotion of M2 polarization, contributing to its anti-rheumatoid arthritis effects. Likewise, these findings originate from animal-level studies, with the mechanisms remaining unverified in humans. The precise targets of MAG, the pathways of signal cross-regulation, and potential adverse effects warrant further comprehensive research. At the same time, sustained Nrf2 activation could impact normal immune responses, necessitating the development of targeted modulation approaches.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial nuclear receptor involved in the regulation of lipid metabolism and inflammation. As a ligand-dependent transcription factor, it plays an essential role in immune regulation, inflammation suppression, and metabolic balance, with particular importance in the development and treatment of RA (Geng et al., 2024). In the synovial tissue of RA patients, reduced PPARγ expression correlates closely with the proinflammatory status (Li et al., 2023). This phenomenon may be attributed to PPARγ activation inhibiting NF-κB and AP-1 activity, reducing proinflammatory cytokine secretion, and directly promoting M2 gene expressio (Liu S. et al., 2021).

Astragaloside IV (AS-IV), a natural saponin derived from the botanical drug Astragalus, can activate the PPARγ pathway to enhance fatty acid oxidation, induce M2 macrophage polarization, and stimulate IL-10 and TGF-β production, thereby promoting macrophage-mediated repair and significantly reducing joint inflammation in RA (Xiong et al., 2025). However, pharmacokinetic and pharmacodynamic studies investigating its efficacy in RA treatment are still lacking. Bavachinin (BVC), a natural plant metabolite isolated from Cullen corylifolium, possesses a wide range of pharmacological properties such as antitumor, anti-inflammatory, antioxidant, antimicrobial, antiviral, and immunomodulatory effects. According to Deng et al. (2023), BVC suppresses MH7A cell proliferation, migration, and inflammatory mediator production through the PPARγ/PI3K/AKT signaling pathway, thereby reducing joint injury and inflammation in CIA mice. Unfortunately, no studies to date have reported on its in vivo efficacy. Given that PPARγ serves as a central target at the intersection of metabolism and inflammation, its ligands must be developed with consideration for balancing anti-inflammatory and metabolic modulation.

AMP-activated protein kinase (AMPK) signaling serves as a key modulator of energy metabolism and plays a broad role in regulating metabolic processes, inflammation, and cell proliferation (Herzig and Shaw, 2018). In RA, AMPK activation can inhibit the abnormal proliferation and migration of RA fibroblast-like synovial cells (RA-FLS), and reduce the release of inflammatory mediators such as TNF-α and IL-6, thereby alleviating joint damage; simultaneously, AMPK can regulate the RANKL-OPG bone protective factor pathway to inhibit bone destruction (Qiu et al., 2021). Moreover, AMPK activation inhibits glycolysis, promotes fatty acid oxidation, and induces M2 polarization by suppressing mTOR (Cui et al., 2023).

Berberine, a prominent anti-inflammatory alkaloid derived from the rhizome of Coptis chinensis, acts by activating AMPK, suppressing mTORC1, promoting mitochondrial oxidative phosphorylation, and reducing glycolytic metabolites such as lactate. It induces M2 macrophage polarization and inhibits the NLRP3 inflammasome through AMPK activation, thereby attenuating pyroptosis-associated inflammation and contributing to overall inflammation relief (Cheng et al., 2023). Naringenin, a naturally occurring flavonoid present in numerous plants, exhibits potent anti-inflammatory and immune-regulating properties. According to research by Zhang et al. (2023) and colleagues, Naringenin mitigates joint inflammation in CIA models by activating the AMPK/ULK1 pathway, reducing the release of pro-inflammatory cytokines, and boosting antioxidant defenses. Therefore, the AMPK pathway can integrate metabolic and inflammatory signals, and its activation by plant metabolites may restore immunometabolic homeostasis in RA.

STAT6, an important signaling molecule in the STAT (signal transducer and activator of transcription) family, is mainly activated by cytokines like IL-4 and IL-13. It plays a critical role in immune responses, allergic diseases, and chronic inflammatory diseases (Cai et al., 2019). Evidence indicates that the IL-4/IL-13/STAT6 pathway contributes significantly to RA pathogenesis IL-4 and IL-13 induce STAT6 phosphorylation to promote M2 macrophage polarization, suppress the release of pro-inflammatory mediators, and enhance the expression of markers such as Arg1 and FIZZ1, thereby supporting tissue regeneration and reducing inflammation (Parveen et al., 2025).

The natural flavonoid luteolin possesses potent anti-inflammatory activity; by upregulating p-STAT6 and downregulating p-STAT3, it promotes the transition from M1 to M2 macrophages and effectively alleviates joint inflammation in RA (Gu et al., 2024; Zhu et al., 2024). Suberosin (SBR), extracted from the plant Plumbago zeylanica L., has demonstrated anti-inflammatory and immunomodulatory properties. Liu et al. (2025) and colleagues found in animal experiments that SBR can inhibit JAK1/STAT3 while promoting JAK1/STAT6 phosphorylation, enhance M2 polarization, and alleviate arthritis in CIA mice. In summary, the promise of these plant-derived metabolites necessitates additional clinical evaluation and the development of approaches to address their poor bioavailability. The balanced regulation of STAT6 and STAT3 is critical for maintaining M1/M2 macrophage equilibrium, and the bidirectional modulatory effects of plant metabolites warrant further investigation.