Yujie Jin1,2,3†Yongxin Cui1,2,3†Zhanyan Zhang3,4†Chenglin Huang3†Ruoting Tong3,4Ye Ling3,4Qirui Pei3,4Yan Ma3,4Qixia Zhan5Xiaojian Leng5Junjun He1,2,3Lizhuo Wang3,4*
Jialin Gao1,2,3*- 1Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
- 2Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
- 3Anhui Province Key Laboratory of Basic Research and Transformation of Age-Related Diseases, Wannan Medical College, Wuhu, Anhui, China
- 4Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu, Anhui, China
- 5Guangde People's Hospital, Xuancheng, Anhui, China
Tripterygium glycosides (TG), bioactive extracts derived from Tripterygium wilfordii Hook F., possess potent anti-inflammatory and immunomodulatory properties, making them promising therapeutic candidates for a range of autoimmune and inflammatory diseases. This review summarizes recent advances in the pharmacological mechanisms of TG, including their roles in cytokine suppression, autophagy modulation, anti-fibrotic remodeling, and oxidative stress regulation. Evidence from clinical trials and real-world studies supports the therapeutic potential of TG in conditions such as systemic lupus erythematosus, diabetic kidney disease, rheumatoid arthritis, and psoriasis. In addition, we highlight ongoing efforts to overcome TG's narrow therapeutic window through monomer isolation, structural optimization, prodrug strategies, and innovative delivery systems. Emerging derivatives—such as LLDT-8 (5R-5-hydroxytriptolide) and triptonide—exhibit reduced toxicity while retaining robust efficacy, providing new avenues for clinical translation. Furthermore, the integration of systems pharmacology, synthetic biology, and AI-assisted drug design is accelerating the development of next-generation TG-based therapeutics.
1 Introduction
Tripterygium wilfordii Hook F. (TwHF), also known as Thunder God Vine, is a long-standing herb in traditional Chinese medicine (TCM) and has been used for centuries to treat chronic inflammatory and autoimmune disorders. Among its various bioactive constituents, Tripterygium glycosides (TG)—a partially purified extract standardized from TwHF—have attracted increasing interest in modern pharmacological research. TG consists of multiple diterpenoids, triterpenoids, and alkaloids, and is widely used in clinical practice in China for conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and chronic kidney diseases, particularly lupus nephritis and IgA nephropathy (1, 2).
Over the past two decades, substantial experimental and clinical evidence has demonstrated that TG exerts its therapeutic effects through multiple molecular and cellular mechanisms. These include inhibition of pro-inflammatory pathways (e.g., NF-κB, JAK/STAT, MAPK), modulation of immune cell activation (e.g., T cells, B cells, macrophages), and suppression of pro-fibrotic signaling cascades (e.g., TGF-β/Smad). Notably, TG also appears to modulate autophagy, attenuate oxidative stress, and induce apoptosis in aberrant immune or stromal cells. Together, these pleiotropic actions position TG as a unique immunomodulatory agent with broad translational potential (3). Recently, TG has regained significant research attention for its potential therapeutic applications in diabetic kidney disease (DKD), especially in cases where traditional therapies, such as renin–angiotensin–aldosterone system inhibitors and SGLT2 inhibitors, do not fully halt disease progression. Emerging evidence suggests that TG exerts anti-proteinuric, anti-inflammatory, and anti-fibrotic effects in DKD, thereby addressing important unmet clinical needs (4). Moreover, TG has demonstrated synergistic benefits when combined with modern therapies, providing a compelling rationale for its integration into combination treatment regimens.
Despite its clinical promise, the therapeutic window of TG remains narrow, and its dose-limiting toxicities—particularly hepatotoxicity, reproductive toxicity, and gastrointestinal intolerance—have hindered broader global adoption. To address these limitations, recent efforts have focused on optimizing TG formulations, developing targeted delivery systems, and identifying predictive biomarkers of toxicity to improve patient safety. Additionally, several TG-derived monomer compounds, such as triptolide and celastrol, are undergoing structural modification and preclinical evaluation to enhance efficacy while reducing toxicity (5). Given its complex pharmacology, evolving clinical utility, and the urgent need for safer and more effective immunoregulatory agents, TG represents a promising yet underutilized candidate for drug development. This review aims to summarize the latest advances in TG's mechanisms of action, therapeutic applications across multiple disease domains, safety challenges, and emerging innovation strategies that may help bridge the gap between its traditional use and modern global pharmaceutical development.
2 Pharmacological mechanisms of Tripterygium glycosides
TG exerts its therapeutic effects through multiple, interrelated pharmacological mechanisms. These include immune modulation, anti-inflammatory actions, anti-fibrotic effects, and the regulation of autophagy, apoptosis, and oxidative stress (Figure 1).
Figure 1. This figure summarizes the mechanism of action, clinical applications, safety issues and optimization strategies of Tripterygium glycosides. The drugs exert multi-target immunomodulatory and anti-inflammatory effects by targeting pathways such as NF-κB and MAPK, and can also regulate autophagy, fibrosis and oxidative stress. Clinical evidence supports their application in autoimmune diseases such as systemic lupus erythematosus, diabetic nephropathy, rheumatoid arthritis and psoriasis. However, their narrow therapeutic window, hepatotoxicity and reproductive toxicity and other safety issues limit their wide application. Structural optimization through the identification of active monomers (such as triptolide), prodrug delivery strategies and the development of safer derivatives (such as LLDT-8) can improve their therapeutic index and clinical translation potential.
2.1 Immunomodulation and cytokine suppression
TG demonstrates potent immunosuppressive activity by attenuating excessive immune responses through multiple signaling cascades. These mechanisms collectively underpin TG's therapeutic efficacy in autoimmune disorders such as RA and SLE.
TG exerts significant anti-inflammatory effects by suppressing the NF-κB and MAPK signaling pathways. In macrophages and T lymphocytes, TG reduces the phosphorylation of IKK and IκBα, thereby inhibiting the nuclear translocation of NF-κB p65 and decreasing the transcription of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 (6). Additionally, TG inhibits the phosphorylation of MAPK family members, including ERK1/2 and p38, thereby attenuating AP-1 activation and further reducing inflammatory gene expression (7). In a diabetic nephropathy rat model, TG reduced glomerular macrophage infiltration and downregulated TNF-α, IL-1β, and TGF-β1 expression through suppression of the p38 MAPK and NF-κB signaling pathways. Emerging evidence suggests that TG also dampens the JAK/STAT pathway in T lymphocytes, thereby mitigating cytokine-driven proliferation. In collagen-induced arthritis models, TG and its monomer triptolide restored the Th17/Treg balance through inhibition of the JAK/PTEN–STAT3 axis, consequently suppressing IL-17 and IL-23 production.
TG promotes immune homeostasis by modulating T-cell differentiation and B-cell function. It enhances the frequency and suppressive capacity of regulatory T cells (Tregs) while inhibiting Th17 lineage commitment, thereby shifting the immune equilibrium toward a more tolerogenic state (8). In RA and SLE preclinical models, TG increased FoxP3 expression in CD4? T cells and reduced ROR γ t-driven Th17 responses, decreasing IL-17 release. Network pharmacology research supports TG's suppression of Th17 differentiation and IL-17 signaling in autoimmune skin disease models (9). TG also interferes with antigen presentation by inhibiting dendritic cell maturation and B-cell activation. TG extracts reduce the expression of dendritic cell co-stimulatory molecules (CD80 and CD86) and suppress cytokine production (e.g., IL-12 and IL-23), thereby impairing Th1/Th17 priming and attenuating antibody-mediated immune responses (10). These concerted immunoregulatory effects—namely, the suppression of pro-inflammatory signaling pathways, modulation of T- and B-cell balance, and inhibition of antigen presentation—form the mechanistic foundation for TG's clinical applications in autoimmune and inflammatory diseases (11).
2.2 Anti-inflammatory and anti-fibrotic effects
TG exhibits strong anti-inflammatory and anti-fibrotic properties across various disease models, including renal, hepatic, pulmonary, and dermal fibrosis.
In DKD models, TG markedly reduces proteinuria, glomerulosclerosis, and renal inflammation. Mechanistically, TG suppresses the activation of p38 MAPK and NF-κB signaling, thereby diminishing glomerular macrophage infiltration and downregulating the expression of pro-inflammatory cytokines (TNF-α, IL-1β) as well as the pro-fibrotic mediator TGF-β1 (2). Meta-analyses confirm a significant reduction in proteinuria and serum creatinine in diabetic nephropathy patients treated with TG compared to control groups (12). Moreover, in Adriamycin-induced nephropathy, TG suppresses activation of the TGF-β1/Smad signaling pathway, downregulates Smad2/3 phosphorylation, and reverses epithelial–mesenchymal transition (EMT), thereby alleviating glomerulosclerosis and tubulointerstitial fibrosis (13). TG also attenuates fibrosis through suppression of the TGF-β/Smad signaling pathway, a central regulator of fibrogenesis. In models of renal interstitial fibrosis, TG decreases TGF-β1 secretion, reduces Smad2/3 phosphorylation, and upregulates the inhibitory mediator Smad7, thereby dampening the pro-fibrotic transcriptional program. These molecular effects are accompanied by reduced deposition of collagen I/III and fibronectin within the renal interstitium (13, 14). Similar anti-fibrotic efficacy has been observed in fibrotic models of liver and skin, supporting TG's broad-spectrum anti-fibrotic potential.
TG restores autophagic flux—crucial for inhibiting fibrogenesis—particularly in kidney injury models. In diabetic nephropathy, triptolide (a TG monomer) reactivates autophagy through the PTEN/Akt/mTOR signaling axis, triggering reduction of extracellular matrix and fibrotic markers via miR-141-3p modulation (15). Activation of AMPK/mTOR by TG further enhances autophagy, supporting cellular homeostasis and reducing ECM accumulation. These autophagy-dependent effects are instrumental in mediating TG's anti-fibrosis action. TG exerts antioxidant effects by attenuating reactive oxygen species (ROS) and promoting endogenous antioxidant responses (e.g., Nrf2/HO-1). This antioxidant action synergizes with TGF-β/Smad pathway inhibition to effectively mitigate oxidative stress-induced fibrotic signaling, such as ERK and p38 MAPK activation, further enhancing tissue repair and reducing fibrosis progression (2, 15).
2.3 Autophagy regulation
TG, particularly its active constituent triptolide, exerts a profound regulatory effect on autophagy—a cellular process essential for maintaining homeostasis, degrading damaged organelles, and preventing fibrogenic transformation. Restoration of autophagy is a key mechanism underlying the therapeutic efficacy of TG in DKD, systemic inflammation, and fibrosis.
In DKD, impaired podocyte autophagy contributes to glomerular injury, proteinuria, and disease progression. TG restores autophagic flux by increasing the LC3-II/LC3-I ratio and decreasing p62 expression, molecular markers indicative of enhanced autophagy and lysosomal activity (16). These changes are associated with increased nephrin and podocin expression, improved cytoskeletal integrity, and reduced apoptosis in glomerular epithelial cells (17). The PTEN/Akt/mTOR signaling cascade plays a central role in the regulation of autophagy. Under hyperglycemic conditions, PTEN expression is suppressed, leading to overactivation of Akt and mTORC1 and subsequent inhibition of autophagy. TG counteracts this effect by upregulating PTEN, reducing Akt phosphorylation, and inhibiting mTORC1, thereby reactivating autophagy (15). In vitro and in vivo studies confirm that TG alleviates renal fibrosis and EMT through this pathway by promoting the degradation of fibrotic components and reducing TGF-β1 expression (15, 18).
In renal tubular epithelial cells, TG suppresses EMT by modulating the mTOR/Twist1 axis. Specifically, TG downregulates phosphorylated mTOR and Twist1, a key transcription factor that drives mesenchymal transition. This regulatory effect restores autophagic activity, reduces the expression of vimentin and α-SMA, and preserves epithelial markers such as E-cadherin (19). TG may also activate AMPK, a central energy sensor that antagonizes mTORC1. While the AMPK–mTOR interaction has been well established in the actions of other renoprotective agents, TG appears capable of engaging this pathway as well, particularly under metabolic stress conditions. This dual inhibition of mTOR signaling—through PTEN activation and AMPK engagement—enhances autophagic responsiveness and improves cellular adaptation to injury (20).
2.4 Oxidative stress and apoptosis
TG plays a dual role in regulating oxidative stress and apoptosis, two processes that are essential for maintaining cellular integrity and facilitating the removal of damaged or pathogenic cells. TG modulates intracellular ROS levels, activates endogenous antioxidant pathways, and selectively induces apoptosis in cells that are damaged or inflamed.
TG exerts antioxidative activity by attenuating excessive ROS production while enhancing cellular antioxidant defenses (21). However, studies show that triptolide—the principal active component of TG—can suppress the expression of Nrf2 and its downstream targets HO-1 and NQO1 in models exposed to both LPS and triptolide, thereby exacerbating oxidative injury in zebrafish liver. These findings suggest a context- and dose-dependent effect of TG on redox balance (22). Consistently, TG-induced hepatotoxicity in mice has been associated with downregulation of Nrf2/HO-1 and Bcl-2, along with increased Bax expression and lipid peroxidation, indicating that TG can reduce oxidative stress at therapeutic doses but may promote oxidative injury at higher or non-physiological concentrations (23). TG promotes apoptosis in pathogenic or stress-affected cells through mitochondrial- and ER-mediated pathways. Triptolide induces mitochondrial outer membrane permeabilization (MOMP), leading to cytochrome c release and activation of caspase-3 and caspase-9, thereby shifting the Bax/Bcl-2 balance toward apoptosis in immune and renal cell (24). Furthermore, TG aggravates ER stress by increasing ROS production and disrupting redox homeostasis, thereby activating unfolded protein response (UPR) pathways and inducing CHOP-mediated caspase cascades in models such as osteosarcoma cells and Sertoli cells.
TG-induced oxidative stress robustly activates MAPK family members—particularly JNK and p38—ultimately leading to mitochondrial dysfunction and apoptotic signaling. For example, ROS accumulation enhances JNK phosphorylation, which in turn promotes mitochondrial pore formation, cytochrome c release, and downstream caspase activation in reproductive and hepatic cell models (25). TG's pro-apoptotic activity exhibits notable selectivity: malignant cells, activated immune cells (e.g., dendritic cells), and fibrotic cells are considerably more susceptible than their healthy counterparts. This selective cytotoxicity is attributed to their intrinsically higher basal levels of ROS and ER stress, which render these cells more vulnerable to TG-induced oxidative perturbation and mitochondrial collapse (26).
2.5 Network pharmacology
Network pharmacology offers a systems-level perspective on how TG and TwHF-derived compounds interact with multiple molecular targets across diverse signaling pathways, thereby elucidating their multifaceted therapeutic effects in inflammatory, fibrotic, and autoimmune diseases.
A network pharmacology analysis evaluating TwHF in DKD identified 68 overlapping targets between TG bioactive constituents and DKD-associated genes. Key hub targets included PTGS2, RELA (NF-κB p65), AKT1, and MAPK8 (JNK). Enrichment analysis further highlighted several pivotal pathways—such as AGE–RAGE, IL-17, TNF, and insulin resistance—aligning well with the established multi-pathway regulatory actions of TG (27). In membranous nephropathy (MN), network pharmacology models identified 126 overlapping gene targets, implicating key pathways such as AGE–RAGE signaling, lipid metabolism, IL-17, and NF-κB—closely mirroring the immuno-inflammatory axes observed in DKD. Molecular docking analyses further demonstrated strong binding affinities between TG constituents and core targets such as PTGS2 and RELA, with docking energies below −5 kJ/mol, thereby reinforcing the relevance of these pathways in mediating TG's renoprotective effects (28). In SLE, network pharmacology analyses identified TG-mediated regulation of inflammatory and fibrotic signaling pathways, including NF-κB, STAT1/2, and Th17-related targets. Enrichment analysis highlighted pathways such as cytokine–cytokine receptor interaction and apoptosis. Key hub targets—including JAK1/2, STAT3, and TLR4—were also identified, consistent with the established immunomodulatory and anti-inflammatory effects of TG in experimental SLE models..
Investigations into Tripterygium hypoglaucum (a closely related species) have revealed overlapping molecular targets associated with both therapeutic efficacy—such as STAT3, VEGFA, and MMP9—and toxicity, including TP53 and components of the p53 signaling pathway. Network pharmacology analyses further highlighted the PI3K–Akt and p53 pathways as critical intersections between beneficial and adverse effects (29). These findings underscore the need to refine TG formulations to preserve therapeutic potency while minimizing toxicity risks, particularly hepatotoxicity and reproductive injury. Combined transcriptomic and metabolomic analyses of TwHF in DKD have validated predictions from network pharmacology, demonstrating that TG modulates key pathways including AGE–RAGE, TNF, IL-17, and insulin resistance. Molecular docking further confirmed strong binding affinities of TG constituents—such as kaempferol and triptolide—to core targets including PTGS2 and AKT1 (30). Together, these findings establish a robust mechanistic framework that integrates computational prediction with experimental validation.
3 Clinical applications
TG has been extensively evaluated in clinical settings, demonstrating therapeutic efficacy across autoimmune, renal, dermatologic, and ophthalmologic disorders. Below is a refined overview organized by disease domain, with emphasis on evidence from randomized controlled trials (RCTs) and meta-analyses (Figure 2).
Figure 2. Multi-target mechanisms of Tripterygium glycosides (TG) in immune and metabolic diseases. TG exert therapeutic effects by inhibiting key inflammatory pathways (NF-κB, MAPK, and JAK/STAT), modulating immune cell balance, and restoring autophagy via PTEN/Akt/mTOR and AMPK signaling. TG also suppresses TGF-β/Smad-mediated fibrosis and oxidative stress, and induces selective apoptosis through mitochondrial and endoplasmic reticulum (ER) stress pathways. Network pharmacology highlights the multi-target interactions of TG in diseases such as diabetic kidney disease and systemic lupus erythematosus, supporting its broad therapeutic potential.
3.1 Systemic lupus erythematosus
TG have shown promising efficacy as an adjunctive treatment in SLE, particularly in reducing disease activity and immunosuppressant dependence. A meta-analysis including eight RCTs with 538 SLE patients found that TG combined with conventional therapy significantly reduced disease activity (mean difference in SLEDAI = −1.66 [95% CI −2.07 to −1.26]) and improved overall response rate (RR = 1.21 [95% CI 1.11–1.32]) compared to conventional therapy alone (31). Importantly, the incidence of adverse events—including gastrointestinal discomfort and mild elevations in liver enzymes—did not differ significantly between TG and control groups, supporting its short-term safety and tolerability. Additional systematic reviews and real-world clinical studies have further corroborated these findings (31, 32). TG not only improves serologic markers—such as reducing anti-dsDNA antibodies and increasing complement C3 and C4 levels—but also shows potential glucocorticoid-sparing effects and may help reduce the risk of lupus flares as disease activity decreases (31).
Natural compounds primarily ameliorate SLE by inhibiting NF-κB and JAK/STAT signaling, restoring Treg/Th17 balance, and reducing autoantibody production, thereby attenuating systemic inflammation. Recent mechanistic investigations have revealed that triptolide, the major active constituent of TG, modulates immune dysregulation in SLE through several convergent pathways (31). Triptolide corrects the abnormal distribution of Th and Tc effector T-cell subsets observed in lupus models, thereby mitigating dysfunctional T-cell skewing. Within germinal center–related immunity, triptolide restores the balance between follicular regulatory T cells (Tfr) and follicular helper T cells (Tfh) (33), effectively limiting excessive B-cell help, restraining aberrant germinal center activation, and reducing autoantibody production. At the B-cell–intrinsic level, triptolide upregulates miR-146a, a key negative regulator of the TLR7 signaling pathway, thereby attenuating TLR7-driven B-cell hyperactivation and reducing the generation of pathogenic autoantibodies (34).
Given its dual impact on inflammation and immune dysregulation, TG is increasingly regarded as a potential steroid-sparing agent in lupus management. Nevertheless, long-term safety evaluations and large-scale randomized controlled trials conducted outside of East Asia are still required to substantiate these findings and facilitate broader regulatory acceptance worldwide.
3.2 Diabetic kidney disease
Many natural compounds have demonstrated renoprotective effects in DKD by acting on several convergent molecular pathways. Recent evidence shows that these agents commonly inhibit NF-κB–mediated inflammation, suppress TGF-β/Smad-driven fibrotic signaling (35, 36), reduce renal macrophage infiltration, and restore impaired podocyte autophagy—mechanisms that align closely with key pathological drivers of DKD progression (37–39). Against this mechanistic background, TG have gained increasing attention as a complementary therapy in DKD, particularly in patients with persistent proteinuria despite standard RAAS blockade. A randomized, controlled clinical trial in DKD demonstrated that Tripterygium wilfordii extracts significantly reduced 24-hour urinary protein and improved overall clinical response compared with conventional treatment alone (40). Consistent findings were observed in a meta-analysis of stage IV DKD, where TG therapy further decreased proteinuria and increased serum albumin levels while maintaining an acceptable safety profile (41). Together, these clinical data support the adjunctive use of TG in proteinuric DKD, especially in patients who show suboptimal response to RAAS inhibition.
Mechanistically, recent studies have shown that triptolide confers renoprotection in DKD by modulating microRNA-dependent pathways that govern autophagy and fibrotic progression. Triptolide restores impaired autophagy in diabetic kidneys by suppressing miR-141-3p, thereby releasing PTEN from microRNA-mediated inhibition and subsequently downregulating the Akt/mTOR signaling cascade, a key suppressor of autophagic activity. Reestablishment of PTEN–Akt/mTOR signaling improves autophagic flux and ultimately reduces renal fibrotic injury in DKD models (15). In parallel, triptolide attenuates tubular EMT—a central mechanism driving tubulointerstitial fibrosis—through inhibition of miR-188-5p, leading to suppression of the PI3K/Akt pathway and downstream mesenchymal markers such as α-SMA and vimentin, while preserving epithelial characteristics (42). Taken together, these findings suggest that triptolide alleviates DKD by simultaneously enhancing autophagy and suppressing EMT through two distinct microRNA–Akt regulatory axes.
From a safety perspective, adverse events such as gastrointestinal discomfort, transient hepatotoxicity, and menstrual disturbances were more common in TG-treated groups, although serious toxicity was rare (32). Although no standardized safety threshold has been established, clinical experience and available trials suggest that lower daily doses and limiting treatment duration may help reduce TG-related adverse events (43). Given the unmet need for effective anti-proteinuric therapies beyond SGLT2 inhibitors and GLP-1 receptor agonists, TG represents a promising adjunctive option, particularly in resource-limited settings or among patients who are intolerant of standard treatments. Nevertheless, long-term randomized controlled trials with robust renal endpoints (e.g., eGFR slope, progression to dialysis) and comprehensive real-world safety data are urgently required to define TG's therapeutic role in global DKD management.
3.3 Rheumatoid arthritis
RA is a chronic autoimmune disorder characterized by persistent synovial inflammation and progressive joint damage (44–46). Current management emphasizes early diagnosis and timely initiation of disease-modifying anti-rheumatic drugs (DMARDs) to prevent structural deterioration. Standard treatment follows a stepwise strategy, starting with conventional synthetic DMARDs such as methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine (47). Patients with inadequate response are advised to escalate to biologic DMARDs targeting TNF-α, IL-6R, or CTLA-4-Ig, or to targeted synthetic DMARDs such as Janus kinase inhibitors, to achieve optimal disease control (48).
In parallel, TCM has been widely incorporated into RA management in China, particularly for patients with chronic pain, intolerance to immunosuppressive therapy, or preference for integrative medicine. TG have gradually become a cornerstone herbal therapy in the clinical management of RA in China and are increasingly recognized for their potent anti-inflammatory and immunomodulatory properties. Multiple meta-analyses demonstrate that TG is non-inferior to MTX—the first-line conventional DMARD—in improving key clinical endpoints such as joint swelling, morning stiffness, pain scores, and erythrocyte sedimentation rate (ESR) (49). A meta-analysis including 11 randomized controlled trials with 1,675 RA patients evaluated Tripterygium wilfordii preparations and showed that they increased overall clinical effectiveness by approximately 20% and reduced the risk of adverse events by about 18%, with markedly greater improvements in ESR, RF, and CRP compared with control treatments (50). Moreover, combining TG with MTX or leflunomide produces synergistic therapeutic benefits without markedly increasing adverse events, supporting TG as an effective adjunctive strategy for moderate to severe RA (51).
In RA, natural compounds generally suppress NF-κB, MAPK, and JAK/STAT pathways, reduce IL-1β, IL-6, and TNF-α levels, and inhibit fibroblast-like synoviocyte proliferation, leading to improved synovial inflammation and joint protection (52, 53). Mechanistically, Tripterygium-derived compounds suppress RA inflammation primarily by inhibiting the IL-17/NF-κB signaling pathway, leading to marked reductions in IL-17, TNF-α, IL-6, and IL-1β levels in synovial tissues. They also restrain the pathological proliferation of fibroblast-like synoviocytes by downregulating CDK2 and restoring p21, while promoting apoptosis through increased caspase-3 and reduced Bcl-2/Bax ratios. Together, these actions correct synovial hyperplasia and help mitigate joint inflammation and damage (50, 54). Despite its therapeutic benefits, TG is limited by dose-related gastrointestinal discomfort, menstrual irregularities, leukopenia, and hepatotoxicity. Systematic reviews indicate that short-term regimens of approximately 1 mg/kg/day (not exceeding 1.5 mg/kg/day, divided into three post-meal doses) generally show acceptable safety, whereas higher doses or prolonged use markedly increase toxicity. Chinese expert consensus therefore positions TG as an adjunctive or alternative csDMARD for patients intolerant of, or unresponsive to, conventional DMARDs (55). However, most clinical studies originate from China, and the lack of high-quality international trials continues to restrict TG's incorporation into Western treatment guidelines.
3.4 Psoriasis and skin disorders
TG has shown therapeutic benefit in moderate-to-severe plaque psoriasis (PsV), offering a potential alternative or adjunct to agents such as acitretin and cyclosporine. In a randomized trial enrolling 115 PsV patients treated for 8 weeks, both TG and acitretin significantly reduced PASI scores, but TG demonstrated a better safety profile, with fewer mucocutaneous reactions, lipid abnormalities, and liver enzyme elevations. Although not statistically significant, a higher proportion of patients achieved PASI-50 with TG than with acitretin (50% vs. 43%) (56).
Most natural compounds improve psoriasis by inhibiting the IL-23/IL-17 axis and NF-κB/MAPK signaling, thereby reducing Th17-mediated inflammation and normalizing keratinocyte proliferation (57, 58). Further evidence from combination therapy trials suggests that TG may exert synergistic effects when used with acitretin. In one study involving 36 patients, the combination of TG and acitretin led to superior PASI score reductions and more stable liver function parameters compared to acitretin monotherapy (59). Although a subsequent retraction raised concerns regarding data integrity, the hypothesis of additive benefit remains plausible and is supported by TG's known mechanisms of action. Mechanistically, TG suppresses Th17 cell differentiation, inhibits IL-17 and TNF-α signaling, and downregulates dendritic cell activation—pathways central to psoriatic inflammation (9). Triptolide, a major active constituent of TG, has also been shown to promote Treg cell differentiation, further contributing to immune homeostasis in psoriatic lesions (60).
Short-term TG therapy ( ≤ 8 to 12 weeks) in psoriasis is generally well tolerated, with adverse events mainly limited to mild gastrointestinal discomfort and reversible menstrual irregularities. No severe hepatotoxicity or nephrotoxicity has been reported under controlled dosing conditions. However, broader dermatologic use remains limited by the lack of large, multicenter RCTs, uncertainties regarding long-term safety, and batch-to-batch variability in TG preparations. Consequently, further high-quality evidence is required before TG can be routinely incorporated into international dermatologic practice.
3.5 Ophthalmologic and neuroinflammatory disorders
Emerging clinical and preclinical evidence suggests that TG may offer therapeutic benefit in ocular autoimmune and neuroinflammatory diseases, particularly in Graves' orbitopathy (GO) (61, 62) and experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS) (1).
Growing evidence from systematic reviews and meta-analyses indicates that TG may provide clinical benefit in patients with active thyroid-associated orbitopathy (TAO). A comprehensive meta-analysis of Chinese cohorts reported that TG, either as monotherapy or in combination with low-dose glucocorticoids, was associated with significant reductions in clinical activity score (CAS), improvements in soft-tissue inflammation, and, in some studies, modest improvements in proptosis and extraocular muscle involvement. Another systematic review similarly concluded that TG-based regimens improved overall clinical response rates and disease inactivation compared with conventional therapies (61, 62). These findings indicate that TG may serve as a corticosteroid-sparing agent in GO, providing a well-tolerated oral option for patients with contraindications to IVMP or concerns about steroid-related toxicity.
Natural compounds mitigate neuroinflammation by suppressing microglial activation and NF-κB/MAPK pathways, reducing IL-17A and TNF-α production, and improving blood–brain barrier integrity (53). In the realm of neuroinflammatory diseases, triptolide—the primary active component of TG—has demonstrated efficacy in attenuating neuroinflammation in EAE models. Mechanistic studies indicate that triptolide reduces BBB permeability, suppresses microglial activation, and downregulates pro-inflammatory cytokines such as IL-17A and TNF-α within the central nervous system (63). Additionally, experimental evidence demonstrates that triptolide suppresses Th17 cell infiltration while enhancing regulatory T cell (Treg) proliferation within the spinal cord microenvironment, suggesting its potential in limiting demyelination and neurodegeneration (53, 64). While these preclinical data are promising, clinical trials of TG or triptolide in multiple sclerosis or other neuroimmune disorders remain lacking, and concerns about CNS toxicity must be thoroughly addressed.
Although data in these indications are limited, the targeted immunosuppressive profile of TG, along with its ability to modulate T-cell responses and cytokine networks, provides a rationale for further investigation in ophthalmic and neuroinflammatory settings. Well-designed clinical trials and mechanistic translational research are required to determine optimal dosing parameters, safety profiles, and CNS penetration of TG in human subjects.
4 Toxicity profiles, safety challenges, and barriers to clinical translation
TG possess strong therapeutic potential across multiple immune-mediated and inflammatory diseases; however, their clinical utility is constrained by a narrow safety margin and notable systemic toxicities. These challenges have prompted intensive research efforts focused on three major directions: mitigating inherent toxicities, refining molecular structures to improve the therapeutic window, and developing advanced delivery systems to enhance targeted distribution. This section synthesizes current progress in toxicity reduction strategies and the development of safer TG-derived compounds, providing a foundation for their broader clinical translation (Figure 3; Table 1).
Figure 3. The disease-specific mechanisms of Tripterygium glycosides. In systemic lupus erythematosus, TG inhibits NF-κB and JAK/STAT signaling and restores Treg/Th17 balance; in diabetic kidney disease, it suppresses TGF-β/Smad signaling, reduces macrophage infiltration, and restores podocyte autophagy; in rheumatoid arthritis, TG downregulates IL-6, IL-1β, and TNF-α to alleviate synovial inflammation; in psoriasis, it inhibits Th17 differentiation and IL-17/TNF-α signaling; and in neuroinflammatory disorders, TG reduces microglial activation and improves blood–brain barrier integrity.
Table 1. Comparative toxicity profiles, mechanistic features, and therapeutic windows of triptolide, LLDT-8, and triptonide.
4.1 Toxicity and clinical toxicity-related failures
Despite its proven therapeutic efficacy, TG are associated with a narrow therapeutic window and a well-recognized spectrum of dose- and time-dependent toxicities. The most frequently reported adverse effects include gastrointestinal symptoms (nausea, diarrhea, abdominal discomfort), menstrual irregularities, hepatic dysfunction, leukopenia, and reproductive toxicity. In pharmacovigilance studies and real-world cohort analyses, the incidence of adverse events varies between 20–40% (65), but serious toxicity remains relatively rare when TG is administered at ≤ 1.5 mg/kg/day for a treatment duration under 3–6 months (43, 66). Hepatotoxicity is usually transient and reversible but warrants regular monitoring of liver enzymes (ALT, AST). Hematologic abnormalities, such as leukopenia or thrombocytopenia, may occur and necessitate temporary drug withdrawal or dose reduction. Reproductive toxicity—including oligospermia and menstrual suppression—is dose-related and often reversible upon discontinuation but remains a major concern in younger patients or those seeking fertility (32).
Nevertheless, these toxicities have led to clinically meaningful treatment discontinuation, particularly in real-world cohorts and randomized trials. In SLE and RA studies, gastrointestinal reactions, elevated liver enzymes, and leukopenia were among the leading causes of early withdrawal, while dose-related reproductive toxicity—such as oligospermia and menstrual suppression—prompted discontinuation in younger patients or those concerned about fertility (50, 66). Beyond routine clinical practice, toxicity has also contributed to translational failures of TG-derived monomers. Multiple early-phase international development attempts involving triptolide were terminated due to severe gastrointestinal injury, hepatocellular toxicity, or bone-marrow suppression, preventing advancement into late-stage trials. In addition, batch-to-batch variability in TG preparations has resulted in inconsistent toxicity profiles, further limiting global adoption (67–69). Collectively, these toxicity-related clinical and translational failures highlight the need for standardized formulations, stringent monitoring, and the development of safer TG derivatives.
4.2 Challenges in translating preclinical toxicity to clinical settings
Although animal studies provide essential insights into the organ-specific and dose-dependent toxicity of TG and triptolide, several challenges significantly limit the direct translation of these findings to clinical practice. First, species differences in metabolic pathways profoundly influence the bioactivation and clearance of diterpenoids. Rodents metabolize triptolide through hepatic CYP isoforms that differ from those predominant in humans, leading to discrepancies in systemic exposure and hepatotoxicity thresholds (70). Second, dose–exposure relationships vary substantially between animals and humans. Many preclinical toxicity studies employ supratherapeutic or bolus doses to demonstrate organ injury, whereas clinical dosing is typically lower, fractionated, and influenced by interindividual variability, comorbidities, and concomitant therapies (71). Third, animal models often fail to recapitulate human susceptibility factors, such as pre-existing liver disease, reproductive hormonal fluctuations, gut microbiota–mediated drug metabolism, and genetic polymorphisms in detoxification enzymes—all of which modulate TG toxicity in real-world populations (72). Additionally, the composition of TG preparations used in animal experiments may not match clinical formulations. Variability in extraction methods, triptolide content, and the presence of other diterpenoids contributes to inconsistent toxicity patterns that may not faithfully represent human exposure. Finally, animal studies typically have short observation windows and cannot fully capture chronic toxicity, cumulative reproductive impairment, or long-term immunosuppression, which are clinically relevant concerns in autoimmune diseases (68). Collectively, these translational gaps underscore the need for rigorous pharmacokinetic bridging, standardized formulations, and carefully monitored clinical dosing strategies to safely apply preclinical toxicity data to human therapy.
4.3 Comparative toxicity profiles and the therapeutic window problem
Tripterygium-derived monomers differ substantially in their toxicity profiles, therapeutic indices, and organ-specific adverse effects (68). Triptolide, the most potent bioactive constituent of TG, also exhibits the narrowest therapeutic window, with dose-dependent hepatic, reproductive, and hematologic toxicities. In contrast, next-generation derivatives such as LLDT-8 (5R-5-hydroxytriptolide) and triptonide demonstrate expanded safety margins owing to structural modifications that attenuate off-target cytotoxicity while preserving key immunomodulatory activities.
Triptolide serves as the reference point for toxicity comparison (73). As the primary driver of TG-related adverse events, triptolide exerts potent inhibition of transcriptional processes and mitochondrial function. These actions lead to hepatocellular injury (via excessive ROS production, mitochondrial depolarization, and impaired autophagy flux), reproductive toxicity (Sertoli cell apoptosis, disrupted spermatogenesis, menstrual suppression), and hematologic suppression (leukopenia and bone-marrow inhibition) (74, 75). This constellation of toxicities defines the pharmacologic constraints that newer derivatives aim to overcome.
LLDT-8 (5R-5-hydroxytriptolide) represents one of the most successful attempts to mitigate triptolide-associated toxicity (76). Preclinical evidence indicates that LLDT-8 achieves comparable or even superior immunomodulatory efficacy in SLEand RA models (77), yet exhibits markedly reduced cytotoxicity toward hepatocytes and Sertoli cells (78). Mechanistically, LLDT-8 diminishes mitochondrial ROS accumulation and stabilizes mitochondrial membrane potential, leading to lower hepatotoxic and reproductive risk. Importantly, LLDT-8 retains inhibition of NF-κB and STAT3 signaling while promoting Treg expansion with less activation of apoptotic pathways (79), which has enabled its progression into phase I/II clinical trials for lupus nephritis and idiopathic inflammatory myopathy (67).
Triptonide, a naturally occurring C14 epimer lacking triptolide's epoxide moiety (67), demonstrates an even more favorable safety profile (80). Elimination of the C14 epoxide—recognized as a key structural determinant of hepatic and reproductive toxicity—significantly attenuates triptonide's impact on liver function and fertility (67). Comparative toxicology studies show that triptonide induces substantially less Sertoli cell apoptosis, exhibits lower IC50 hepatocyte toxicity, and causes fewer sperm abnormalities than triptolide (67, 81). Despite this improved tolerability, triptonide maintains potent immunoregulatory and anti-inflammatory properties. SAR analyses further confirm that modifications at the epoxide, C14 hydroxyl, and lactone ring positions critically influence the balance between efficacy and toxicity (67).
Collectively, these comparative data define a clear toxicity hierarchy—triptolide > LLDT-8 > triptonide—illustrating how rational molecular modification can markedly expand the therapeutic window of TG-derived diterpenoids. Continued comparative toxicology and mechanistic profiling will be essential for identifying the most promising candidates for clinical translation and for guiding the development of safer, next-generation TG-based therapeutics.
4.4 Regulatory barriers and gaps limiting global acceptance
Despite promising therapeutic potential, TG and their derivatives face significant regulatory barriers that limit global acceptance. The lack of standardized extraction processes and batch-to-batch consistency remains a major obstacle, as variability in triptolide content directly affects both efficacy and toxicity (32, 65). Furthermore, toxicology data for TG extracts are often heterogeneous, derived from mixed formulations, or insufficiently aligned with modern regulatory expectations for purity-defined small molecules. The absence of internationally harmonized quality-control frameworks, combined with incomplete long-term safety data and limited Phase II/III trial evidence, has prevented broader approval outside China. Concerns regarding reproductive toxicity, hepatotoxicity, and dose–response variability further contribute to regulatory hesitancy (32, 74), especially in regions with stringent pharmacovigilance requirements. Additionally, the incomplete mechanistic elucidation of off-target toxicities and the lack of validated biomarkers for monitoring TG-induced adverse effects constitute remaining gaps (32). Addressing these issues through standardization, rigorous toxicology profiling, and globally compliant clinical development pathways will be essential for advancing TG-based therapeutics toward wider international adoption.
5 Future perspectives and global translation of TG-based therapeutics
Future development of TG-based therapeutics requires high-quality mechanistic and clinical evidence, standardized safety management, and globally harmonized quality control. Although TG show broad immunomodulatory and antifibrotic potential, their translation is limited by intrinsic diterpenoid toxicity and formulation variability. Advances in monomer identification, structural optimization, and targeted delivery—together with emerging technologies such as AI-assisted design and biosynthetic engineering—are paving the way for safer, more precise next-generation TG derivatives. These innovations collectively outline a clearer path toward global adoption of TG-based therapies.
5.1 Novelty and limitations of this review
This review provides an integrated and cross-disciplinary perspective on TG by systematically linking their multi-target pharmacological mechanisms with clinical applications across autoimmune, renal, dermatologic, and neuroinflammatory diseases. Unlike previous reviews that typically focus on a single disease or on triptolide alone, our work offers several novel contributions. First, we comparatively analyze disease-specific mechanistic pathways and highlight areas of convergence—such as NF-κB, JAK/STAT, TGF-β/Smad, and autophagy regulation—that collectively explain TG's broad therapeutic spectrum. Second, we provide one of the most detailed summaries to date of toxicity-related failures, derivative optimization strategies, and structure–toxicity relationships, including comparative toxicity profiles of next-generation monomers such as LLDT-8 and triptonide. Third, we outline a forward-looking framework for TG standardization, monomer differentiation, and structural refinement that may inform future drug-development pipelines.
Nevertheless, this review has inherent limitations. Evidence supporting TG efficacy and safety remains heterogeneous, with most randomized trials being small, single-center, or conducted exclusively in Chinese populations. Mechanistic studies across diseases vary in depth, and some conclusions rely on preclinical data that may not fully translate to humans. Additionally, long-term safety data, standardized toxicology protocols, and globally harmonized quality-control criteria for TG preparations are insufficient, limiting definitive assessment of therapeutic windows and regulatory feasibility. These gaps highlight the need for large, multi-ethnic clinical trials, rigorous pharmacokinetic and toxicology profiling, and international consensus on quality standards to advance TG-based therapeutics toward global acceptance.
5.2 Clinical risk-mitigation strategies and safety management
To mitigate these risks, several risk management strategies have been proposed and implemented in clinical practice. First, individualized dosing and duration control are essential. Most guidelines recommend limiting the cumulative dose and total course duration, especially in combination regimens. Baseline assessments (e.g., liver/renal function, complete blood count, pregnancy testing) and periodic monitoring (every 2–4 weeks during the initial phase) are advised to detect early signs of toxicity (55). Second, co-administration with hepatoprotective agents or leukopoiesis-supportive therapies (e.g., leucogen) has been explored with partial success in observational studies (65). Third, the development of TG monomer derivatives with improved selectivity and reduced toxicity profiles is actively ongoing and may represent the next generation of TG-based therapeutics (67). Furthermore, the standardization of TG extracts and quality control across manufacturers are critical for ensuring consistent bioavailability and minimizing unexpected toxicity due to formulation variability (82). Lastly, patient education on early warning signs (e.g., fatigue, bleeding, jaundice, menstrual delay) is an integral part of safe TG administration.
While clinical risk-mitigation strategies can reduce the incidence of adverse reactions during TG therapy, they do not fundamentally address the intrinsic toxicity of major diterpenoids such as triptolide. Therefore, substantial efforts have been directed toward optimizing molecular structures and developing next-generation TG derivatives to overcome the narrow therapeutic window (Figure 3).
5.3 Technology-driven innovation, regulatory challenges, and global translation
To overcome the narrow therapeutic window of TG, recent research has focused on a multi-tiered safety-optimization framework that integrates monomer identification, structural optimization, prodrug engineering, and targeted delivery. These methods collectively aim to retain TG's potent anti-inflammatory and immunomodulatory activities while reducing the intrinsic toxicity of diterpenoid components such as triptolide (Figure 4).
Figure 4. Toxicity, risk management, and derivative development of TG. This figure highlights TG's main toxicities—gastrointestinal, hepatic, and reproductive—and strategies to improve safety, including short-term use, monitoring, and extended-release formulations. Structural optimization and derivative development focus on reducing toxicity while preserving efficacy.
First, monomer identification has become a foundational strategy for improving safety. Recent analytical advances—including bioactivity-guided fractionation, metabolomic profiling, and network-based target analysis—have demonstrated that only a small subset of TG diterpenoids meaningfully contributes to therapeutic activity (83), while many structurally reactive constituents are responsible for disproportionate toxicity. Studies consistently show that key bioactive monomers such as triptolide, celastrol, tripdiolide, and wilforgine possess defined immunomodulatory and anti-inflammatory mechanisms, whereas epoxide-rich or highly electrophilic diterpenoids exhibit stronger hepatotoxic (84), reproductive, and hematologic toxicity due to their high chemical reactivity and low target selectivity. Structural analyses further reveal that the C14–C15 epoxide of triptolide represents a major toxicophore, and its removal yields derivatives with markedly improved safety (67). By distinguishing efficacy-driving monomers from toxicity-dominant components, monomer identification enables selective enrichment of beneficial constituents and reduction of harmful ones, effectively widening the therapeutic window at the formulation level (Figure 5).
Figure 5. This figure summarizes the four interconnected pillars supporting the development of safer and more translatable TG-based therapeutics. Clinical risk mitigation focuses on dose control, structured monitoring, supportive co-therapies, and standardized patient education. Monomer identification differentiates efficacy-driving diterpenoids from toxicity-dominant components and defines key structural toxicophores to improve formulation-level safety. Structural optimization employs rational chemical modifications—such as epoxide removal, reduced electrophilicity, and targeted medicinal-chemistry refinements—to generate next-generation derivatives with lower systemic toxicity. Targeted delivery strategies, including PEGylated prodrugs, albumin-binding conjugates, and inflammation-responsive nanocarriers, help decouple pharmacodynamic activity from systemic exposure and broaden the therapeutic window. Together, these four dimensions outline a coherent roadmap for advancing TG derivatives toward safer clinical application and global translation.
Second, structural optimization of key diterpenoids has become the most effective strategy to intrinsically suppress toxicity. SAR studies consistently identify the C14 α-epoxide of triptolide as the dominant toxicophore, driving mitochondrial injury, oxidative stress, apoptosis, and reproductive toxicity (68, 85). Removing or modifying this epoxide—as exemplified by triptonide—markedly reduces systemic toxicity while preserving core immunosuppressive activity. Selective hydroxylation represents another successful approach. LLDT-8 maintains strong inhibition of NF-κB and STAT3 but induces substantially less oxidative and mitochondrial stress, confirming that fine-tuning reactive functional groups can widen the safety margin without compromising efficacy (86). Beyond these representative derivatives, additional medicinal-chemistry refinements—such as lactone-ring modification, redox-group replacement, and stereochemical adjustments—have produced compounds with lower electrophilicity, improved metabolic stability, and reduced off-target reactivity (85). These structural strategies, together with emerging targeted-delivery and prodrug systems, have enabled several optimized derivatives to advance into preclinical or early clinical evaluation, underscoring their promise as safer next-generation Tripterygium agents (85, 86).
Third, multiple delivery platforms—including PEGylated triptolide prodrugs (87), albumin-binding conjugates, and inflammation-responsive nanoparticles—have been shown to markedly reduce peak systemic exposure while enhancing tissue selectivity (88). PEGylated and albumin-binding formulations extend circulation time and modulate release kinetics, thereby lowering hepatic accumulation and minimizing off-target toxicity (88). Inflammation-targeted nanocarriers further improve drug deposition in diseased tissues by exploiting microenvironmental cues such as enhanced vascular permeability and macrophage uptake (87). Together, these engineered systems effectively decouple pharmacodynamic activity from systemic exposure, enabling therapeutic concentrations to be achieved at inflamed or fibrotic sites with substantially reduced systemic toxicity and thereby broadening the therapeutic window of triptolide-based agents (89).
Together, these optimization strategies illustrate a clear developmental trajectory toward safer TG-derived therapeutics. By combining monomer-level refinement, rational structural redesign, and advanced delivery technologies, next-generation TG derivatives are progressively overcoming the intrinsic toxicity barriers that have historically limited their clinical adoption.
Author contributions
YJ: Conceptualization, Methodology, Validation, Writing – original draft. YC: Conceptualization, Methodology, Validation, Writing – original draft. ZZ: Conceptualization, Methodology, Validation, Writing – original draft. CH: Investigation, Writing – original draft. RT: Conceptualization, Methodology, Validation, Writing – original draft. YL: Methodology, Visualization, Writing – original draft. QP: Conceptualization, Supervision, Writing – original draft. YM: Conceptualization, Supervision, Writing – original draft. QZ: Validation, Writing – review & editing. XL: Methodology, Writing – original draft. JH: Methodology, Writing – original draft. LW: Funding acquisition, Project administration, Resources, Writing – review & editing. JG: Funding acquisition, Project administration, Resources, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This research was funded by the National Natural Science Foundation of China (82370808), the “Climbing Peak” Training Program for Innovative Technology Team of Yijishan Hospital, Wannan Medical College (PF2019013), the “Peak” Training Program for Scientific Research of Yijishan Hospital, Wannan Medical College (GF2019J07), Major Project Funding from the Anhui Provincial Education Department (2023AH040244, 2023AH040245) the Clinical Medical Research Transformation Project of Anhui Province (202204295107020067), the Anhui Provincial Health and Medical Research Project Major Program jointly supported by the Commission and the Province with Provincial Financial Support (2024BAC50001).
Acknowledgments
The authors sincerely thank the Institute of Endocrine and Metabolic Diseases and the Anhui Province Key Laboratory of Basic and Translational Research on Age-related Diseases for providing essential technical support and scientific advice. We further appreciate the contributions of our colleagues at the Department of Endocrinology and Genetic Metabolism, First Affiliated Hospital of Wannan Medical College, whose assistance in discussion, data review, and experimental operations has greatly enriched this work. We also acknowledge the generous funding support described above, which played an indispensable role in enabling the successful completion of this study.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
TG, Tripterygium glycosides; TwHF, Tripterygium wilfordii hook F.; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; DKD, diabetic kidney disease; PASI, psoriasis area and severity index; EMT, epithelial–mesenchymal transition; ECM, extracellular matrix; FLS, fibroblast-like synoviocytes; Treg, regulatory T cell; Th17, T helper 17 cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; JAK, Janus kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; TGF-β, transforming growth factor beta; Smad, small mothers against decapentaplegic; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homolog; ROS, reactive oxygen species; Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, Heme oxygenase-1; ER, endoplasmic reticulum; UPR, unfolded protein response; GO, Graves' orbitopathy; EAE, experimental autoimmune encephalomyelitis; CNS, central nervous system; RCT, randomized controlled trial; HPLC, high-performance liquid chromatography; SAR, structure–activity relationship; GMP, good manufacturing practice.
References
1. Shan Y, Zhao J, Wei K, Jiang P, Xu L, Chang C, et al. A comprehensive review of Tripterygium wilfordii Hook F. in the treatment of rheumatic and autoimmune diseases: bioactive compounds, mechanisms of action, and future directions. Front. Pharmacol. (2023) 14:1282610. doi: 10.3389/fphar.2023.1282610
2. Wu W, Yang J-J, Yang H-M, Huang M-M, Fang Q-J, Shi G, et al. Multi-glycoside of Tripterygium wilfordii Hook F. attenuates glomerulosclerosis in a rat model of diabetic nephropathy by exerting anti-microinflammatory effects without affecting hyperglycemia. Int J Mol Med. (2017) 40:721–30. doi: 10.3892/ijmm.2017.3068
3. Wang Y, Jia L, Wu CY. Triptolide inhibits the differentiation of Th17 cells and suppresses collagen-induced arthritis. Scand J Immunol. (2008) 68:383–90. doi: 10.1111/j.1365-3083.2008.02147.x
4. Long L, Yu J, Jin J, Zhang J. Metabolomics based exploration of the mechanism of action of Tripterygium glycosides in diabetic kidney disease. Biomed Chromatogr. (2025) 39:e70071. doi: 10.1002/bmc.70071
5. Ding Z, Wang X, Zhang Y, Liu J, Wan L, Li T, et al. Altered iron-mediated metabolic homeostasis governs the efficacy and toxicity of Tripterygium glycosides tablets against rheumatoid arthritis. Engineering. (2024) 39:166–79. doi: 10.1016/j.eng.2024.04.003
6. Yang J, Li T-X, Wang X-Y, Xue Z-P, Lyu C, Li H-Z, et al. Systematic reviews of effects of Tripterygium glycosides tablets on pro-inflammatory factors in rheumatoid arthritis. Zhongguo Zhong yao za zhi. (2020) 45:764–74. doi: 10.19540/j.cnki.cjcmm.20191024.401
7. Xiao H-R, Ma H-Q, Wu C-C. Protective effect of Tripterygium glycosides on ulcerative colitis rats based on Erk/P38 mapk signaling pathway. Zhongguo Zhong yao za zhi. (2024) 49:5281–7. doi: 10.19540/j.cnki.cjcmm.20240624.401
8. Ji W, Li H, Gao F, Chen Y, Zhong L, Wang D. Effects of Tripterygium glycosides on interleukin-17 and Cd4+ Cd25+ Cd127low regulatory T-Cell expression in the peripheral blood of patients with ankylosing spondylitis. Biomed Rep. (2014) 2:517–20. doi: 10.3892/br.2014.262
9. Chen Y, Wang YF, Song SS, Zhu J, Wu LL Li XY. Potential shared therapeutic and hepatotoxic mechanisms of Tripterygium wilfordii polyglycosides treating three kinds of autoimmune skin diseases by regulating Il-17 signaling pathway and Th17 cell differentiation. J Ethnopharmacol. (2022) 296:115496. doi: 10.1016/j.jep.2022.115496
10. Zhu KJ, Shen QY, Cheng H, Mao XH, Lao LM, Hao GL. Triptolide affects the differentiation, maturation and function of human dendritic cells. Int Immunopharmacol. (2005) 5:1415–26. doi: 10.1016/j.intimp.2005.03.020
11. Bao J, Dai SM. A Chinese herb Tripterygium wilfordii Hook F. in the treatment of rheumatoid arthritis: mechanism, efficacy, and safety. Rheumatol Int. (2011) 31:1123–9. doi: 10.1007/s00296-011-1841-y
12. Guo HB, Peng JQ, Xuan W, Zhang KK, Zhong GZ, Chen WH, et al. Efficacy of Tripterygium glycosides for diabetic nephropathy: a meta-analysis of randomized controlled trials. BMC Nephrol. (2021) 22:304. doi: 10.1186/s12882-021-02487-8
13. Wan YG, Che XY, Sun W, Huang YR, Meng XJ, Chen HL, et al. Low-dose of multi-glycoside of Tripterygium wilfordii Hook F., a natural regulator of Tgf-β1/smad signaling activity improves adriamycin-induced glomerulosclerosis in vivo. J Ethnopharmacol. (2014) 151:1079–89. doi: 10.1016/j.jep.2013.12.005
14. Jiao H, Zhang M, Chen L, Zhang Z. Traditional Chinese medicine targeting the Tgf-Beta/smad signaling pathway as a potential therapeutic strategy for renal fibrosis. Front Pharmacol. (2025) 16:1513329. doi: 10.3389/fphar.2025.1513329
15. Li XY, Wang SS, Han Z, Han F, Chang YP, Yang Y, et al. Triptolide restores autophagy to alleviate diabetic renal fibrosis through the Mir-141-3p/Pten/Akt/Mtor pathway. Mol Ther Nucleic Acids. (2017) 9:48–56. doi: 10.1016/j.omtn.2017.08.011
16. Gong J, Jin J, Zhao L, Li Y, Li Y, He Q. Tripterygium glycoside protects against puromycin amino nucleoside-induced podocyte injury by upregulating autophagy. Int J Mol Med. (2018) 42:115–22. doi: 10.3892/ijmm.2018.3598
17. Liang S, Jin J, Shen X, Jiang X, Li Y, He Q. Triptolide protects podocytes via autophagy in immunoglobulin a nephropathy. Exp Ther Med. (2018) 16:2275–80. doi: 10.3892/etm.2018.6480
18. Cao Y, Huang X, Fan Y, Chen X. Protective effect of triptolide against glomerular mesangial cell proliferation and glomerular fibrosis in rats involves the Tgf-Beta 1/smad signaling pathway. Evid Based Complement Alternat Med. (2015) 2015:814089. doi: 10.1155/2015/814089
19. Tao M, Zheng D, Liang X, Wu D, Hu K, Jin J, et al. Tripterygium glycoside suppresses epithelial-to-mesenchymal transition of diabetic kidney disease podocytes by targeting autophagy through the Mtor/Twist1 pathway. Mol Med Rep. (2021) 24:592. doi: 10.3892/mmr.2021.12231
20. Wang X, Zhang Y, Ding Z, Du L, Zhang Y, Yan S, et al. Cross-talk between the Ras–Erk and Mtor signalings-associated autophagy contributes to Tripterygium glycosides tablet-induced liver injury. Biomed Pharmacother. (2023) 160:114325. doi: 10.1016/j.biopha.2023.114325
21. Ma B, Zhong Y, Chen R, Zhan X, Huang G, Xiong Y, et al. Tripterygium glycosides reverse chemotherapy resistance in ovarian cancer by targeting the Nrf2/Gpx4 signal axis to induce ferroptosis of drug-resistant human epithelial ovarian cancer cells. Biochem Biophys Res Commun. (2023) 665:178–86. doi: 10.1016/j.bbrc.2023.04.111
22. Li C, Zhang C, Zhu C, Zhang J, Xia Q, Liu K, et al. Inflammation aggravated the hepatotoxicity of triptolide by oxidative stress, lipid metabolism disorder, autophagy, and apoptosis in zebrafish. Front Pharmacol. (2022) 13:949312. doi: 10.3389/fphar.2022.949312
23. Liu C-F, Zhang J-X, Li Y-Q, Li C, Zhu X-X, Jia K-X, et al. Effects of Tripterygium glycosides tablets from 6 different manufacturers on acute liver injury of normal mice. Zhongguo Zhong yao za zhi. (2019) 44:3494–501. doi: 10.19540/j.cnki.cjcmm.20190715.401
24. Yan Y, Xu Z, Wang C, Liu Y, Long Y, Yuan X, et al. Natural compound triptolide induces caspase-3/Gsdme-mediated pyroptosis by promoting ros accumulation in small cell lung cancer. Cancer Cell Int. (2025) 25:426. doi: 10.1186/s12935-025-04071-8
25. Chen H, Chen X, Ma J. The mitigation mechanism of hesperidin on deoxynivalenol toxicity in grass carp hepatocytes via decreasing Ros accumulation and inhibiting jnk phosphorylation. Fish Shellfish Immunol. (2023) 134:108646. doi: 10.1016/j.fsi.2023.108646
26. Wu H, Chen Z, Chen J-Z, Pei L-G, Xie J, Wei Z-H, et al. High mobility group B-1 (Hmgb-1) promotes apoptosis of macrophage-derived foam cells by inducing endoplasmic reticulum stress. Cell Physiol Biochem. (2018) 48:1019–29. doi: 10.1159/000491970
27. Wang Y, Liu T, Ma F, Lu X, Mao H, Zhou W, et al. A network pharmacology-based strategy for unveiling the mechanisms of Tripterygium wilfordii Hook F. against diabetic kidney disease. J Diabetes Res. (2020) 2020:2421631. doi: 10.1155/2020/2421631
28. Xu P, Fu G, Zhao H, Wang M, Ye H, Shi K, et al. Review of molecular biological research on the treatment of membranous nephropathy with Tripterygium glycosides based on Tcm theory. Medicine. (2023) 102:e34686. doi: 10.1097/MD.0000000000034686
29. Yang S, Wang M, Li Z, Luan X, Yu Y, Jiang J, et al. Tripterygium wilfordii Hook F. induced kidney injury through mediating inflammation via Pi3k-Akt/Hif-1/Tnf signaling pathway: a study of network toxicology and molecular docking. Medicine. (2024) 103:e36968. doi: 10.1097/MD.0000000000036968
30. Lu M, Ou J, Deng X, Chen Y, Gao Q. Exploring the pharmacological mechanisms of Tripterygium wilfordii against diabetic kidney disease using network pharmacology and molecular docking. Heliyon. (2023) 9:e17550. doi: 10.1016/j.heliyon.2023.e17550
31. Chen Y, Wang L, Li N, Zhou C. Tripterygium glycosides for safely controlling disease activity in systemic lupus erythematosus: a systematic review with meta-analysis and trial sequential analysis. Front Pharmacol. (2023) 14:1207385. doi: 10.3389/fphar.2023.1207385
32. Ru Y, Luo Y, Zhou Y, Kuai L, Sun X, Xing M, et al. Adverse events associated with treatment of Tripterygium wilfordii Hook F.: a quantitative evidence synthesis. Front Pharmacol. (2019) 10:01250. doi: 10.3389/fphar.2019.01250
33. Zhao X, Ji W, Lu Y, Liu W, Guo F. Triptolide regulates the balance of Tfr/Tfh in lupus mice. Adv Rheumatol. (2023) 63:29. doi: 10.1186/s42358-023-00311-5
34. Zhang Y, Zhang F, Gao Y, Wang M, Gao Y, Li H, et al. Triptolide in the treatment of systemic lupus erythematosus—regulatory effects on Mir-146a in B cell Tlr7 signaling pathway in mice. Front Pharmacol. (2022) 13:952775. doi: 10.3389/fphar.2022.952775
35. Hong Q, Kim H, Cai GY, Chen XM, He JC, Lee K. Modulation of Tgf-Beta signaling new approaches toward kidney disease and fibrosis therapy. Int J Biol Sci. (2025) 21:1649–65. doi: 10.7150/ijbs.101548
36. He H, Wang H, Chen X, Zhong Y, Huang XR, Ma RCW, et al. Treatment for type 2 diabetes and diabetic nephropathy by targeting Smad3 signaling. Int J Biol Sci. (2024) 20:200–17. doi: 10.7150/ijbs.87820
37. Feng HY, Wang YQ, Yang J, Miao H, Zhao YY Li X. Anthraquinones from rheum officinale ameliorate renal fibrosis in acute kidney injury and chronic kidney disease. Drug Des Devel Ther. (2025) 19:5739–60. doi: 10.2147/DDDT.S521265
38. Chia ZJ, Cao YN, Little PJ, Kamato D. Transforming growth factor-beta receptors: versatile mechanisms of ligand activation. Acta Pharmacol Sin. (2024) 45:1337–48. doi: 10.1038/s41401-024-01235-6
39. Miao H, Wang K-E, Li P, Zhao Y-Y. Rhubarb: traditional uses, phytochemistry, multiomics-based novel pharmacological and toxicological mechanisms. Drug Design Dev Therapy. (2025) 19:9457–80. doi: 10.2147/DDDT.S557114
40. Ge Y, Xie H, Li S, Jin B, Hou J, Zhang H, et al. Treatment of diabetic nephropathy with Tripterygium wilfordii Hook F. extract: a prospective, randomized, controlled clinical trial. J Transl Med. (2013) 11:134. doi: 10.1186/1479-5876-11-134
41. Hong Y, Gui Z, Cai X, Lan L. Clinical efficacy and safety of Tripterygium glycosides in treatment of stage IV diabetic nephropathy: a meta-analysis. Open Med. (2016) 11:611–7. doi: 10.1515/med-2016-0099
42. Xue M, Cheng Y, Han F, Chang Y, Yang Y, Li X, et al. Triptolide attenuates renal tubular epithelial-mesenchymal transition via the Mir-188-5p-mediated Pi3k/Akt pathway in diabetic kidney disease. Int J Biol Sci. (2018) 14:1545–57. doi: 10.7150/ijbs.24032
43. Xie D, Li K, Ma T, Jiang H, Wang F, Huang M, et al. Therapeutic effect and safety of Tripterygium glycosides combined with western medicine on type 2 diabetic kidney disease: a meta-analysis. Clin Ther. (2022) 44:246–56.e10. doi: 10.1016/j.clinthera.2021.12.006
44. Yang C, Chen T, Ma M, Li Q, Liang Z, Xu H, et al. Danggui niantong decoction ameliorates joint inflammation and cardiopulmonary injury in Tnf-Tg mice. Acupunct Herb Med. (2023) 3:333–42. doi: 10.1097/HM9.0000000000000080
45. Xu Y, Zhong L, Liang Q, Xu H. New perspective on the treatment of rheumatic arthritis based on “strengthening body resistance (Fú Zhèng)” in the theory of co-inhibitory receptor-regulated T-cell immunity. Acupunct Herb Med. (2024) 4:290–4. doi: 10.1097/HM9.0000000000000125
46. Pan S, Wu Y-J, Zhang S-S, Cheng X-P, Olatunji OJ, Yin Q, et al. The effect of α7nachr signaling on T cells and macrophages and their clinical implication in the treatment of rheumatic diseases. Neurochem Res. (2021) 47:531–44. doi: 10.1007/s11064-021-03480-1
47. Onuora S. Eular updates its ra management recommendations. Nat Rev Rheumatol. (2020) 16:128. doi: 10.1038/s41584-020-0385-5
48. Szekanecz Z, Buch MH, Charles-Schoeman C, Galloway J, Karpouzas GA, Kristensen LE, et al. Efficacy and safety of Jak inhibitors in rheumatoid arthritis: update for the practising clinician. Nat Rev Rheumatol. (2024) 20:101–15. doi: 10.1038/s41584-023-01062-9
49. Chen K, Chen X, Huang S, Zhou L, Zhou X, Lu Y, et al. Therapeutic effects and mechanisms of Tripterygium wilfordii extracts in rheumatoid arthritis: a systematic review and meta-analysis of preclinical studies. Sci Rep. (2025) 15:27960. doi: 10.1038/s41598-025-13241-7
50. Wang J, Chen N, Fang L, Feng Z, Li G, Mucelli A, et al. A systematic review about the efficacy and safety of Tripterygium wilfordii Hook F. preparations used for the management of rheumatoid arthritis. Evid Based Complementary Altern Med. (2018) 2018:1567463. doi: 10.1155/2018/1567463
51. Feng Z, Fu L, Wang J, Zhu Y, He X, Zhou L, et al. Efficacy of Tripterygium glycosides (Tg) in rheumatoid arthritis as a disease-modifying anti-rheumatic drug (Dmard) in combination with conventional dmards: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. (2022) 184:106405. doi: 10.1016/j.phrs.2022.106405
52. Pillai M, Helen A. Harnessing the immunomodulatory potential of natural products in precision medicine—a comprehensive review. Explor Drug Sci. (2024) 2:339–60. doi: 10.37349/eds.2024.00050
53. Moudgil KD, Venkatesha SH. The anti-inflammatory and immunomodulatory activities of natural products to control autoimmune inflammation. Int J Mol Sci. (2022) 24:24010095. doi: 10.3390/ijms24010095
54. Wang X, Ni T, Miao J, Huang X, Feng Z. The role and mechanism of triptolide, a potential new dmard, in the treatment of rheumatoid arthritis. Ageing Res Rev. (2025) 104:102643. doi: 10.1016/j.arr.2024.102643
55. Lin N, Zhang Y-Q, Jiang Q, Liu W, Liu J, Huang Q-C, et al. Clinical practice guideline for Tripterygium glycosides/Tripterygium wilfordii tablets in the treatment of rheumatoid arthritis. Front Pharmacol. (2021) 11:608703. doi: 10.3389/fphar.2020.608703
56. Wu C, Jin HZ, Shu D, Li F, He CX, Qiao J, et al. Efficacy and safety of Tripterygium wilfordii Hook F. versus acitretin in moderate to severe psoriasis vulgaris: a randomized clinical trial. Chin Med J (Engl). (2015) 128:443–9. doi: 10.4103/0366-6999.151069
57. Elkhawaga OY, Ellety MM, Mofty SO, Ghanem MS, Mohamed AO. Review of natural compounds for potential psoriasis treatment. Inflammopharmacology. (2023) 31:1183–98. doi: 10.1007/s10787-023-01178-0
58. Le S, Wu X, Dou Y, Song T, Fu H, Luo H, et al. Promising strategies in natural products treatments of psoriasis-update. Front Med. (2024) 11:1386783. doi: 10.3389/fmed.2024.1386783
59. And Biomechanics AB. Retracted: Efficacy and safety of Tripterygium wilfordii glycoside tablets combined with acitretin capsules in the treatment of moderate to severe plaque psoriasis: a randomized controlled trial. Appl Bionics Biomech. (2023) 2023:9873802. doi: 10.1155/2023/9873802
60. Han R, Rostami-Yazdi M, Gerdes S, Mrowietz U. Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases. Br J Clin Pharmacol. (2012) 74:424–36. doi: 10.1111/j.1365-2125.2012.04221.x
61. Liu X, Gao C, Liu X, Gao T. Efficacy and safety of Tripterygium glycosides for Graves ophthalmopathy. Medicine. (2019) 98:e18242. doi: 10.1097/MD.0000000000018242
62. Li M, Wei B, Gao T, Gao C. The efficacy of Tripterygium glycosides in the treatment of Chinese patients with thyroid-associated orbitopathy: a systematic review and meta-analysis. Front Pharmacol. (2024) 15:1433791. doi: 10.3389/fphar.2024.1433791
63. Wang H, Zou J, Li Y, Liu J, Guo F. Tripterygium glycoside tablets and triptolide alleviate experimental autoimmune encephalomyelitis mice involving the Pacap/Camp signaling pathway. J Ethnopharmacol. (2025) 347:119748. doi: 10.1016/j.jep.2025.119748
64. Kizelsztein P, Komarnytsky S, Raskin I. Oral Administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis (Eae) by induction of Hsp70 and stabilization of Nf-κb/Iκbα transcriptional complex. J Neuroimmunol. (2009) 217:28–37. doi: 10.1016/j.jneuroim.2009.08.017
65. Zhang C, Sun PP, Guo HT, Liu Y, Li J, He XJ, et al. Safety profiles of Tripterygium wilfordii Hook F.: a systematic review and meta-analysis. Front Pharmacol. (2016) 7:402. doi: 10.3389/fphar.2016.00402
66. Yan X, Shi J, Zhang Y, Liu J, Lin X, Yu C, et al. Effectiveness and safety of Tripterygium wilfordii poly-glycosides on glomerulonephritis: a systematic review and meta-analysis. Front Pharmacol. (2024) 15:1339153. doi: 10.3389/fphar.2024.1339153
67. Gao J, Zhang Y, Liu X, Wu X, Huang L, Gao W. Triptolide: pharmacological spectrum, biosynthesis, chemical synthesis and derivatives. Theranostics. (2021) 11:7199–221. doi: 10.7150/thno.57745
68. Song J, He G-N, Dai L. A comprehensive review on celastrol, triptolide and triptonide: insights on their pharmacological activity, toxicity, combination therapy, new dosage form and novel drug delivery routes. Biomed Pharmacother. (2023) 162:114705. doi: 10.1016/j.biopha.2023.114705
69. Zhang W, Liu X, Xia C, He L, Ma H, Wang X, et al. Case report: a rare case of death due to end-stage renal disease caused by Tripterygium wilfordii-induced myelosuppression. Front Med. (2022) 9:1036422. doi: 10.3389/fmed.2022.1036422
70. Martignoni M, Groothuis GMM, de Kanter R. Species differences between mouse, rat, dog, monkey and human cyp-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. (2006) 2:875–94. doi: 10.1517/17425255.2.6.875
71. Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philos Ethics Human Med. (2009) 4:2. doi: 10.1186/1747-5341-4-2
72. Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol. (2000) 32:56–67. doi: 10.1006/rtph.2000.1399
73. Jiang Q-W, Cheng K-J, Mei X-L, Qiu J-G, Zhang W-J, Xue Y-Q, et al. Synergistic anticancer effects of triptolide and celastrol, two main compounds from thunder god vine. Oncotarget. (2015) 6:32790–804. doi: 10.18632/oncotarget.5411
74. Hang S, Xu L, Wang J, Zhang C, Cao C. Toxicological mechanism of triptolide-induced liver injury. J Biochem Mol Toxicol. (2025) 39:e70319. doi: 10.1002/jbt.70319
75. Hu Y, Wu Q, Wang Y, Zhang H, Liu X, Zhou H, et al. The molecular pathogenesis of triptolide-induced hepatotoxicity. Front Pharmacol. (2022) 13:979307. doi: 10.3389/fphar.2022.979307
76. Liu J, Chen X, Zhang Y, Miao H, Liu K, Li L, et al. Derivatization of (5r)-hydroxytriptolide from benzylamine to enhance mass spectrometric detection: application to a Phase I pharmacokinetic study in humans. Anal Chim Acta. (2011) 689:69–76. doi: 10.1016/j.aca.2011.01.016
77. Guo S, Liu J, Jiang T, Lee D, Wang R, Zhou X, et al. (5r)-5-hydroxytriptolide (Lldt-8) induces substantial epigenetic mediated immune response network changes in fibroblast-like synoviocytes from rheumatoid arthritis patients. Sci Rep. (2019) 9:11155. doi: 10.1038/s41598-019-47411-1
78. Tang W, Zuo J-P. Immunosuppressant discovery from Tripterygium wilfordii Hook F.: the novel triptolide analog (5r)-5-hydroxytriptolide (Lldt-8). Acta Pharmacol Sin. (2012) 33:1112–8. doi: 10.1038/aps.2012.108
79. Zhou R, Zhang F, He P-L, Zhou W-L, Wu Q-L, Xu J-Y, et al. (5r)-5-Hydroxytriptolide (Lldt-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. Int Immunopharmacol. (2005) 5:1895–903. doi: 10.1016/j.intimp.2005.06.009
80. Hansen NL, Kjaerulff L, Heck QK, Forman V, Staerk D, Møller BL, et al. Tripterygium wilfordii cytochrome P450s catalyze the methyl shift and epoxidations in the biosynthesis of triptonide. Nat Commun. (2022) 13:5011. doi: 10.1038/s41467-022-32667-5
81. Chang Z, Qin W, Zheng H, Schegg K, Han L, Liu X, et al. Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates. Nat Commun. (2021) 12:1253. doi: 10.1038/s41467-021-21517-5
82. Wang Y, Dai Z, Yan J, Wu X, Ma S. Comprehensive evaluation of the quality of Tripterygium glycosides tablets based on multi-component quantification combined with an in vitro biological assay. Molecules. (2022) 27:5102. doi: 10.3390/molecules27165102
83. Chen S-R, Dai Y, Zhao J, Lin L, Wang Y, Wang Y. A Mechanistic overview of triptolide and celastrol, natural products from Tripterygium wilfordii Hook F. Front Pharmacol. (2018) 9:104. doi: 10.3389/fphar.2018.00104
84. Li M, Luo Q, Chen X, Qiu F, Tao Y, Sun X, et al. Screening of major hepatotoxic components of Tripterygium wilfordii based on hepatotoxic injury patterns. BMC Compl Med Ther. (2023) 23:9. doi: 10.1186/s12906-023-03836-w
85. Cao Z, Liu B, Li L, Lu P, Yan L, Lu C. Detoxification strategies of triptolide based on drug combinations and targeted delivery methods. Toxicology. (2022) 469:153134. doi: 10.1016/j.tox.2022.153134
86. Cheng Y, Zhao Y, Zheng Y. Therapeutic potential of triptolide in autoimmune diseases and strategies to reduce its toxicity. Chin Med. (2021) 16:114. doi: 10.1186/s13020-021-00525-z
87. Zhu H, Wang Z, Cui J, Ge Y, Yan M, Wu X, et al. Pegylated retinoate prodrug self-assembled nanomicelles loaded with triptolide for targeting treatment of rheumatoid arthritis and side effect attenuation. Colloids Surf B Biointerfaces. (2025) 251:114618. doi: 10.1016/j.colsurfb.2025.114618
88. Yuan Z-x, Jia L, Lim LY, Lin J-c, Shu G, Zhao L, et al. Renal-targeted delivery of triptolide by entrapment in pegylated Trx-20-modified liposomes. Int J Nanomed. (2017) 12:5673-86. doi: 10.2147/IJN.S141095
Keywords: autoimmune diseases, diterpenoids, natural products, structural optimization, translational pharmacology, Tripterygium glycosides, triptolide, triptonide
Citation: Jin Y, Cui Y, Zhang Z, Huang C, Tong R, Ling Y, Pei Q, Ma Y, Zhan Q, Leng X, He J, Wang L and Gao J (2026) Tripterygium glycosides: recent advances in mechanisms, therapeutic applications, and safety optimization. Front. Med. 13:1728162. doi: 10.3389/fmed.2026.1728162
Received: 19 October 2025; Revised: 15 December 2025;
Accepted: 05 January 2026; Published: 02 February 2026.
Edited by:
Xiaoyong Yu, Shaanxi Provincial Hospital of Traditional Chinese Medicine, ChinaReviewed by:
Ahmed A. Al-Amiery, Al-Ayen University, IraqYuli Han, Tianjin University of Traditional Chinese Medicine, China
Copyright © 2026 Jin, Cui, Zhang, Huang, Tong, Ling, Pei, Ma, Zhan, Leng, He, Wang and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jialin Gao, Z2FvamlhbGluLWt0ekB3bm1jLmVkdS5jbg==; Lizhuo Wang, MjAxMTAwNDNAd25tYy5lZHUuY24=
†These authors have contributed equally to this work