In RA synovial tissue, platelet-derived growth factors (PDGF), tumor necrosis factor (TNF), and pro-inflammatory mediators can transform resting FLS cells into an aggressive phenotype associated with glycolysis (RAFLS), known as the “Warburg effect” (Biniecka et al., 2016; Garcia-Carbonell et al., 2016; Masoumi et al., 2020). Hypoxia and high expression of HIF-1α in RA can stimulate the metabolic shift of RAFLS cells from oxidative phosphorylation to glycolysis as HIF-1α can upregulate genes involved in glycolysis, such as GLUT-1, HK-2, and LDH (Masoumi et al., 2020). ENO1 is a rate-limiting enzyme in glycolysis. Under hypoxic conditions, ENO1 gene expression was significantly upregulated in RAFLS and promoted its proliferation. The PGK1 catalyzes the transformation of 1,3-diphosphoglycerate into 3-phosphoglycerate, which results in the production of the first adenosine triphosphate in glycolysis (Zhao et al., 2016). Thus, GLUT1 and HK2 are important modulators of the glucose metabolism. Other glycolysis-related rate-limiting enzymes include, but are not limited to, PFKB3 and PKM2, which have garnered remarkable attention as potential anti-arthritis treatments (Bustamante et al., 2018). Silent information regulator 1 (SIRT1) is an energy sensor that controls associated signals like peroxisome proliferator-activated receptor-γ (PPAR-γ) and maintains metabolic homeostasis; along with deacetylates some signals to prevent their transcriptional activity, like NF-κB and HIF-1α, thereby affecting RA (Wu et al., 2021). Patients with RA exhibit SIRT1 deficiency (Wendling et al., 2014), and the SIRT1 is a negative regulator of glycolysis and M1 macrophage polarization (Lei et al., 2021). Enhancement of the glycolytic metabolic pathway leads to an increase in the lactic acid level. Moreover, further transport of lactic acid into joint lumen can stimulate the phenotype transformation, proliferation, and aggressive metastasis of FLS cells, and increases glycolysis as to accelerate the development of RA, ultimately trigging matrix metalloproteinases and further promoting bone and cartilage destruction (Bottini and Firestein, 2013; Garcia-Carbonell et al., 2016; Masuko, 2022; Pucino et al., 2023) (See green arrow route in Figure 1).

As a natural naphthoquinone isolated from Lithospermum erythrorhizon, shikonin alleviated local joint swelling, and lowered lactate levels in peripheral blood of rats in an AA animal model experiment, along with less toxicity to the liver and kidneys. Mechanistically, shikonin could regulate glycolysis and ATP production by inhibiting GLUT1, PKM2 and HK2 alone, which was verified by knocking down PKM2 expression in RAFLSs. Shikonin has the ability to deactivate mTOR, phosphorylated PI3K and AKT to inhibit PI3K/AKT/mTOR pathway and the primary byproduct of glycolysis, lactate (Lu et al., 2018; Li et al., 2021). Shikonin possesses anti-inflammatory and immunomodulatory properties, but this is the first time proposed that its treatment of RA is related by regulating glycolysis. And there seems to be no relevant literature exploring the efficacy of its combination therapy.

Epigallocatechin-3-gallate (EGCG) from green tea has been demonstrated to have therapeutic efficacy in the treatment of IL-1 receptor antagonist knockdown (IL-1RaKO) autoimmune arthritis rats when administered at 40 mg/kg. In fact, mechanistic studies have found that EGCG administration inhibits the production of indicators of glycolysis and mTOR signaling pathway that support Th17 development, including HIF-1a, GLUT-1, MCT4, LDH-a, and GPI, which contributed to the amelioration of arthritis (Yang et al., 2014). Methotrexate is limited by potential hepatotoxicity in the treatment of RA, and EGCG has been identified to improve MTX-induced hepatotoxicity (Pradhan et al., 2023).

An aberrant metabolism environment of increase in PKM enzyme and lactate expression, a considerable decline in triglycerides and pyruvate were reshaped by resveratrol, a SIRT1 agonist, thereby reducing improper glycolytic metabolism to alleviate symptoms of AIA rats at a dose of 50 mg/kg (Wang DD. et al., 2022). Mechanism studies suggest that the therapeutic effect of SIRT1 may be related to the change of monocyte polarization. Overexpression of SIRT1 dramatically boosts p-AMPK expression while suppressing the aberrant increase in PKM1/2 expression. Simultaneously, it significantly inhibits the expression of HIF-1α and its downstream TPI1, nevertheless, new research has demonstrated that resveratrol induced SIRT1 activation inhibits glycolytic facilitated angiogenesis in RA, irrespective of HIF-1α (Jiang TT. et al., 2023). According to certain research, SIRT1 is typically under-expressed in RA patients. Still, some research has cast doubt on this. Therefore, the development of SIRT1-targeted anti-rheumatic therapy depends on the successful confirmation of this issue. In other research reports, resveratrol has long been considered a potential antioxidant for the treatment of RA, which improves RA by activating the SIRT1-Nrf2 signaling pathway (Wang et al., 2020). Although resveratrol has excellent clinical efficacy, patients with multiple myeloma have reported major side effects (Berman et al., 2017).

α-mangostin extracted from mangosteen can effectively inhibit aerobic glycolysis, restore the level of LDH, and abrogate HIF-1α/VEGF expression in AIA rats when the dose is set at 30 mg/kg/day, thereby alleviating inflammation-related hypoxia. This property of α-mangostin is beneficial in blocking synovial pathologic neovascularization (Jiang et al., 2021). There was a more notable reduction in VEGF in the synovium when α-mangostin therapy was employed in place of the typical DMARD leflunomide. This promising discovery suggested that α-mangostin could be more effective than conventional anti-rheumatic medications in regulating angiogenesis (Zuo et al., 2018; Jiang et al., 2021). In addition to these, in AIA models, α-mangostin has been provided to prevent M1 polarization of macrophages and monocytes by concurrently upregulating SIRT1 and PPAR-γ (Wu et al., 2023), and also to reduce inflammation by interfering with the metabolism-immune feedback system mediated by fat cells (Hu et al., 2021). α-mangostin has been demonstrated to be safe in a variety of animal studies. However, increased doses or repeated dosing should be considered for probable adverse effects such as dysbiosis, cardiac insufficiency, and liver toxicity (Do and Cho, 2020).

High levels of ROS and inflammatory mediators boost glycolysis in M1 macrophages, which causes a buildup of intermediates from the TCA cycle, particularly succinate (Peyssonnaux et al., 2007; West et al., 2011; Mills et al., 2016). By producing IL-1β, succinate has a role in recruiting dendritic cells to lymphoid tissue. Th17 cell releasing factors are activated when succinate upregulates the succinate receptor, Sucnr1/GRP91, intensifying the inflammatory milieu (Littlewood-Evans et al., 2016; Saraiva et al., 2018) and inducing VEGF expression, which results in abnormal angiogenesis (Reddy et al., 2018). Furthermore, inflammation promotes the synthesis of the physiologically active metabolite itaconate, which hinders succinate dehydrogenase’s (SDH) ability to operate as an enzyme and causes succinate buildup. When SDH is blocked, the TCA cycle is disrupted, which encourages the generation of ROS inside the mitochondria, the stabilization of HIF-1α, and the prolonged fermentation of glycolysis within the activated cells (Lampropoulou et al., 2016). (See orange arrow route in Figure 1).

Cinnamon is a TCM used to treat RA. Cinnamaldehyde has been found to alleviate the advancement of RA by modulating the succinate/GPR91/HIF-1α axis to limit NLRP3 activation and IL-1β release when administered at 200 mg/kg in vivo and 12.5 μM in vitro (Liu et al., 2020). Although cinnamaldehyde modifies the generation of succinic acid, its major mechanism of attenuating collagen-induced arthritis is via lowering pro-inflammatory cytokines and free radicals (Mateen et al., 2019). For this reason, cinnamaldehyde primarily serves as an adjuvant in the management of RA.

TGF-β1 stimulation of hypoxia increased succinic acid buildup in the synovium of RA rats by reversing SDH activation, and it also triggered the activation of the NLRP3 inflammasome in a way that was dependent on HIF-1α induction. Clematichinenoside AR, a compound isolated from the root of Clematis manshurica Rupr., inhibits TGF-β1-induced hypoxia and the activation of succinic acid-associated NLRP3 inflammasome in the synovium of RA rats by inhibiting SDH activity, thereby preventing myofibroblast activation via the prevention of a cross-talk between inflammation and fibrosis whose dose at 50 mg/kg (Li et al., 2016). Accordingly, succinate as a metabolic signal could be one of the targets for RA intervention.

With the aggravation of inflammation, the choline pathway, where choline kinase (Chokα) catalyzes the conversion of choline into CDP-choline and subsequent formation of phosphatidylcholine (PC), is highly activated in FLS, resulting in the activation of the regulatory MAPK/PI3K/Akt pathway, MMP expression, and promotion of invasive metastasis of RAFLS cells (Glunde et al., 2011; Guma et al., 2015; Bustamante et al., 2017; Miriam Jose and Rasool, 2022). Correspondingly, the metabolite, 1-oleoyl-sn-glycero-3-phosphocholine (OPGC), in the inhibited choline phospholipid metabolism pathway is downregulated in the plasma of RA patients and participates in the pathogenesis of RA by modulating the IL-6/JAK signaling pathway (Figure 2) (Su et al., 2022). The glycerophospholipid metabolic pathway is markedly dysregulated in RA patients, according to multi-omics research. Acetylcholinesterase (ACHE), one of the key genes, showed a substantial enrichment in the glycerophospholipid pathway. Glycerophosphocholine and inflammatory characteristics have a substantial negative association (Jian et al., 2023).

Network pharmacological studies have shown that Tripterygium wilfordii glycosides (TWG) can target PLA2 and thus interfere with glycerophospholipid metabolism and ether lipid metabolism, resulting in changes in lysoPC and PC levels. The reduction of lyso-PC levels in CIA rats can be corrected treatment with 6 mg/kg TWG per day (Gao et al., 2023). ChoKα has been reported to regulate the tumor-like phenotype of RA-FLS via activating MAPK and PI3K/Akt proteins. In the IL-21-induced tumor-like phenotype assay of AIA-FLS cells, myricetin, a flavonoid, significantly inhibited the high proliferative and invasive potential of AIA-FLSs at an administered concentration of 10 μM. Mechanistically, myricetin inhibited the IL-21/Ras/ChoKα signaling cascade response (Jose and Rasool, 2023).

Lipids are known to contribute to the progression of chronic inflammation, and of the many lipids formed, sphingolipids are thought to be the most deleterious, with their ability to affect bone homeostasis (Seal et al., 2024). Sphingosine (So), sphingosine 1-phosphate (S1P), and ceramide (Cer) are the central molecules of sphingolipid metabolism (Meshcheryakova et al., 2017). Cer promotes chondrocyte apoptosis (Herr and Debatin, 2001). The balance between them is hypothesized to act as a switch that can control whether cells grow or die (Cuvillier et al., 1996). Sphingosine kinase (SphK) phosphorylates So to S1P (Bustamante et al., 2017), and the synovial fluid of RA patients has been found to contain active SphK and high amounts of S1P (Kitano et al., 2006). Two SphK/S1P pathway-regulated mechanisms may be simultaneously involved in the development of RA: inflammation and bone catabolism. S1P stimulates the migration and invasion of FLS, causing synovial thickening and promoting osteoclast formation and synovitis (El Jamal et al., 2020). Under inflammatory conditions, TNF-α activates neutral sphingomyelinase-2 (nSMase-2), resulting in the hydrolysis of sphingomyelin (SM) to Cer, and activates ceramidase (CDase) and SphK, resulting in increased levels of Cer and S1P. The buildup of Cer and S1P promotes the expression of COX-2 and the release of PGE2, which are involved in the pathogenesis of RA, and enhances the MMP response, leading to accelerated bone destruction (Figure 3) (Qu et al., 2018).

According to a study, treatment with T. wilfordii glycosides (TWG, 6 mg/kg) entirely corrected the high Cer levels and markedly decreased the levels of several SM compounds, which has a positive therapeutic effect on RA and inflammation. CDase is required for the conversion of Cer to SM. Some data suggest that TWG can interact with CDase to modulate Cer levels (Zhu et al., 2022). Nevertheless, a growing number of research investigations have demonstrated that T. wilfordii’s active components frequently have adverse consequences including damage of the skin, gastrointestinal, reproductive, blood, and hepatobiliary systems (Lin et al., 2020). Geniposide extracted from Gardenia jasminoides Ellis, when administered 60 mg/kg daily by gavage, can reverse the levels of Cer, palmitoyl ethanolamine, and glycerophospholipid metabolites in AA rats and further reduce inflammation in AA rats by regulating imbalanced sphingolipid metabolism (Zhan et al., 2020; Ke et al., 2022). Changes in geniposide regulated Cer levels were associated with downregulation of A-SMase expression. In addition, geniposide alleviates VEGF-induced angiogenesis by down-regulating S1P/S1PR1 signaling activation (Wang Y. et al., 2022) and attenuates RAFLS aberrant proliferation by preventing HIF-1α accumulation in synovial anoxic microenvironment (Gan et al., 2022).

Cholesterol biosynthetic activity is increased in chondrocytes, which promotes chondrogenesis by preventing apoptosis (Wu and De Luca, 2004). Patients with RA have upregulated cholesterol hydroxylase (CH25H) that facilitates cholesterol biosynthesis and production of more oxysterol metabolites (Perucha et al., 2019). Cellular homeostasis of cholesterol is controlled by end-product feedback mechanisms performed by the sterol regulatory element binding protein (SREBP) pathway (Yan et al., 2021). Cholesterol metabolism was found to exert catabolic functions in chondrocytes by upregulating matrix-degrading enzymes, leading to the development of arthritis (Figure 4) (Choi et al., 2019).

Berberine is hypothesized to suppress the inflammatory proliferation of RAFLSs by modulating AMPK/lipogenesis, LPA/LPA₁/ERK/p38 MAPK (Shen et al., 2020), and ROS-AMPK signaling pathways at 80 μM. TNF-induced RAFLSs overexpress lipid metabolism regulator, SREBP1. Of note, berberine alleviates this expression, thereby reducing the intracellular TNF-stimulated inflammatory proliferation of RAFLSs via mitigating palmitic acid levels (Fan et al., 2018). On the other hand, additional research indicates that the antiarthritic effect of berberine is related to the inhibition of glycolysis. Berberine activates AMPK signaling, downregulates mTORC1/HIF-1α signaling and inhibits the glycolysis of M1 macrophages (Cheng et al., 2023). Berberine reversed the glycolytic reprogramming of CD4⁺ T cells induced by M1-exo (Cai et al., 2024). Although it has previously been found to cross the placenta to cause harmful effects on the fetus and lead to uterine contractions and miscarriage, berberine has not been found to show any cytotoxic or mutagenic effects at the clinical dosages utilized (Bansod et al., 2021). Recent studies have revealed that certain clinical anti-RA medications are used in conjunction with berberine to reduce side effects. To take one example, the combination of berberine and diclofenac sodium can lessen damage to the intestinal mucosa (Huang et al., 2021).

Free fatty acids are present in the serum and synovial fluid of RA patients, and can impact joint tissues and immune cells involved in the pathophysiology of the disease. According to a study, the synovial environment stimulates carnitine abundance in the mitochondrial FAO pathway of human monocytes under hypoxic conditions, which can trigger a CCL20-mediated inflammatory cascade promoting RA pathogenesis (Rodgers et al., 2020). Fatty acids can be metabolized into bioactive lipid mediators, such as pro-inflammatory prostaglandins (PGs), thromboxanes, and leukotrienes (LTs), that can further damage bone and cartilage, and contribute to the pro-inflammatory environment of FLS in RA (Figure 5A) (Lei et al., 2023). Moreover, RA patients have higher activation of PLA enzymes than healthy individuals, which may lead to higher levels of fatty acids and pro-inflammatory effects of the PC/PLA/LPC axis. Studies have shown that PGE2 and the enzymes involved in its production, PLA2 and COX, are more highly expressed in synovial fluid (Figure 5B) (Brouwers et al., 2015). Arachidonic acid (AA) metabolism is involved in the synthesis of PGs and LTs through cyclooxygenase (COX) and lipoxygenase (LOX) to stimulate inflammatory responses (Figure 5B). Recent clinical results suggest that those individuals at risk for ACPA-positive RA show higher levels of LOX-derived oxylipins (O'Neil et al., 2024).

PUFA is one of the metabolite fatty acids of triglycerides that is divided into N6 PUFA with a pro-inflammatory effect and N3 PUFA with an anti-inflammatory effect based on the location and role of the double bond. N3 PUFA can regulate gene expression by activating the peroxisome PPAR-γ (Sun et al., 2008). PPAR-γ has been discovered in rat and human cartilage, and activating PPAR-γ prevents human chondrocytes from producing NO and MMP-13 in response to IL-1 (Fahmi et al., 2001; Yang et al., 2021). Thus, PPAR-γ ligands may be of therapeutic value in RA (Ricote et al., 1998).

Thymoquinone (TQ) has been demonstrated to prevent RA by suppressing COX, LOX, inflammatory cytokines, LPO, and NO (Ali et al., 2021). Thymoquinone has regulatory effects on inflammatory molecular signaling pathways like NF-κβ, JAK-STAT, MAPK signaling, immune cells, and epigenetic machinery (Vaillancourt et al., 2011).

Caffeic acid is a potent inhibitor of LT biosynthesis that blocks 5-LOX activity and AA release, thereby improving RA through its anti-inflammatory and anti-lipid peroxidation actions (Boudreau et al., 2012). Furthermore, caffeic acid ameliorate adjuvant-induced arthritis in rats via targeting inflammatory signals, chitinase-3-like protein-1 and angiogenesis at 50 mg/kg/day for 20 days. Notably, caffeic acid has similar efficacy to celecoxib in alleviating assisted induced arthritis with fewer side effects. These findings may advocate the use of caffeic acid as an adjunct strategy for RA management (Fikry et al., 2019).

An earlier experiment revealed that norisoboldine (NOR), isolated from Linderae Radix, was effective at alleviating arthritic rat conditions when administered orally at a dose of 30 mg/kg. Fang et al. proposed that the anti-arthritic effects of NOR were attributed to the restoration of aberrant lipid metabolism, as demonstrated in detail by the upregulation of carnitine palmitoyltransferase 1 expression and downregulation of fatty acid synthase expression by NOR in the spleen and synovial tissues of CIA rats (Fang et al., 2021).

Isosilybin A, a major bioactive constituent of silymarin, is a partial PPARγ agonist that modifies abnormalities of lipid metabolism and stimulates cholesterol efflux from THP-1 macrophages (Wang et al., 2015). Likewise, Morin (Miao et al., 2022) and ginsenoside Rg1 (Zhang et al., 2017) is medications with PPARγ agonist characteristic that can alleviate RA.

The anti-rheumatic effects of TWG may possibly be attributed to the suppression of pro-inflammatory lipid mediators but the stimulation of certain pro-resolving mediators, and the 5-LOX is a direct target of TWG (Zhang et al., 2021). According to an analysis of the chemical constituents of TWG, 5R-Hydroxytriptolide (LLDT-8) is a novel analog of T. wilfordii-derived triptolide. LLDT-8 regulates the expression of stearoyl-CoA desaturase-1 and PPARγ, which contributes to the promotion of significant degradation of lipids and the inhibition of lipid synthesis. T. wilfordii glycosides have been demonstrated to reduce the inflammatory response by down-regulating PGs, metalloproteinases, and inducible COX-2 in previous investigations (Shan et al., 2023). Despite the fact that these results validate TWG’s advantageous characteristics in treating RA, there is still cause for worry given TWG’s widely recognized toxicity as seen in clinical studies.