Reprogramming Immune Tolerance: A New View of Rheumatoid Arthritis
Rheumatoid arthritis (RA) is commonly described as a chronic inflammatory disease that damages joints. But a more integrated view is emerging from a sustained body of research led by Prof. Vincent Kam Wai Wong at Macau University of Science and Technology: RA may be driven by a breakdown in immune tolerance, in which the body begins to treat its own biological signals as threats.
This has become one of Prof. Wong’s deep research interests. Across related studies, his team has explored how accumulated self-DNA, sex-linked microRNAs, p53-related cellular changes, oxidative stress, calcium imbalance, and abnormal T-cell activation may work together to disturb immune balance. This broader view connects aging biology, sex biology, cancer biology, innate immunity, drug discovery, and cell-free biologic therapy. It also shifts the central question in RA research: rather than asking only how to suppress inflammation, the research team is asking how to restore the immune system’s ability to distinguish self from threat.
Self-DNA as a Trigger of False Alarm
One of the clearest connecting themes is cell-free DNA (cfDNA). As cells age, die, or undergo stress, they release DNA fragments into tissues and blood. Under healthy conditions, these fragments are cleared. When clearance weakens, however, self-DNA can accumulate and trigger a false alarm in the immune system [1], [2].
TREX1, a DNA-degrading enzyme, appears central to this process. Reduced TREX1 activity can allow cfDNA to build up and activate innate immune pathways such as cGAS–STING and TBK1–IRF3, which normally help the body detect infection or cellular danger [1], [3]In RA, these same defense pathways may become harmful when they respond to the body’s own DNA. This mechanism helps explain why aging may increase RA risk and why immune dysregulation may begin before obvious joint destruction.
Importantly, this insight points to a new treatment logic. If cfDNA is not only a marker but also a driver of inflammation, improving DNA clearance could help prevent or reduce RA activity. TREX1-activating compounds such as pterostilbene and bilobalide suggest that upstream control of immune danger signals may complement existing anti-inflammatory therapies [3].
Why RA Differs Between Patients
RA is not the same disease in every patient. Sex, age, immune status, genetic background, and tissue-level changes may all influence disease severity and treatment response. One sex-linked mechanism involves X-chromosome-linked miR-542-5p , which promotes Th17 differentiation, a pro-inflammatory T-cell pathway strongly associated with RA progression [4]. This offers a molecular explanation for why RA affects women more often and why female patients may experience stronger autoimmune activation.
Another important difference lies in the joint tissue itself. RA synovial fibroblasts can become invasive, resistant to cell death, and less responsive to standard drugs. Certain p53 mutations may contribute to resistance to methotrexate and to apoptosis, suggesting that refractory RA can share features with cancer-like cell survival [5]. At the same time, p53-related pathways can interact with innate immune signaling, including TBK1–IRF3–STING, indicating that p53 mutations may shape both drug response and inflammation [6].
Together, these findings strengthen the case for precision RA care. Future diagnosis may need to combine immune, genetic, and tissue-level biomarkers, such as cfDNA, TREX1 activity, miR-542-5p, p53 mutation status, oxidative stress markers, and T-cell signatures, to identify which patients are at risk of aggressive or treatment-resistant disease [2], [4]–[6]
Toward Safer Immune Rebalancing
The same research direction also points to safer, more targeted therapies. IFN-γ-primed mesenchymal stem cell extracellular vesicles may suppress harmful T-cell activation via PD-L1 while protecting bone, offering a cell-free approach to immune regulation [7]. Modified celastrol derivatives may retain anti-arthritic activity through calcium-associated stress signaling while reducing the toxicity of the parent natural compound [8]. The combination of epalrestat with N-acetylcysteine further shows that drug repurposing must consider oxidative and metabolic stress, not only anti-inflammatory effects [9].
These approaches differ in detail but share a common goal: to rebalance immunity rather than simply block it. They suggest that future RA treatment may combine DNA clearance, T-cell regulation, oxidative-stress control, calcium-signaling modulation, and safer biologic or natural-product-based interventions.https://doi.org/10.7150/ijbs.8502
Concluding Remarks
The strongest message from this research cluster is that RA may be understood as a disease of misdirected immune recognition. Aging self-DNA, sex-linked immune activation, p53-associated drug resistance, oxidative stress, calcium signaling, and T-cell checkpoint control all point to a broader field: immune tolerance engineering.
This field has strong clinical and social value. It shifts RA research from late-stage inflammation control to earlier detection, risk prediction, and more personalized intervention. By learning to clear harmful self-signals, restore T-cell balance, and identify patients at risk of aggressive disease [10], future RA care may reduce irreversible joint damage, limit long-term dependence on broad immunosuppression, and improve quality of life before disability becomes permanent.
*Notes: This article provides research teasers for each reference to showcase the novelties
[1] W.-D. Luo et al., “Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis,” Nature Communications, vol. 14, article 4394, 2023. Doi: 10.1038/s41467-023-40113-3.
[2] N. Ma et al., “Targeting age-related cell-free DNA for prevention, early diagnosis and treatment of rheumatoid arthritis,” Autoimmunity Reviews, vol. 25, article 103961, 2026. Doi: 10.1016/j.autrev.2025.103961
[3] Y. Wang et al., “TREX1 activators: A novel therapeutic strategy for rheumatoid arthritis management via cfDNA clearance,” Pharmacological Research, vol. 218, article 107817, 2025. Doi: 10.1016/j.phrs.2025.107817
[4] J. J. Yang et al., “X-chromosome-linked miR-542-5p as a key regulator of sex disparity in rats with adjuvant-induced arthritis by promoting Th17 differentiation,” Biomarker Research, vol. 13, article 36, 2025. Doi: 10.1186/s40364-025-00741-x
[5] C. Qiu et al., “The potential development of drug resistance in rheumatoid arthritis patients identified with p53 mutations,” Genes & Diseases, vol. 10, pp. 2252–2255, 2023. Doi: 10.1016/j.gendis.2023.02.007
[6] Y. Zeng et al., “Mutant p53R211* ameliorates inflammatory arthritis in AIA rats via inhibition of TBK1–IRF3 innate immune response,” Inflammation Research, vol. 72, pp. 2199–2219, 2023. Doi: 10.1007/s00011-023-01809-w.
[7] X. Chen et al., “IFN-γ-primed MSC extracellular vesicles attenuate rheumatoid arthritis via PD-L1-driven T-cell suppression and bone preservation,” Journal of Controlled Release, vol. 395, article 114985, 2026. Doi: 10.1016/j.jconrel.2026.114985.
[8] B. Huang et al., “Celastrol derivatives ameliorate arthritis in AIA rats via modulating calcium signaling,” Phytomedicine, vol. 146, article 157110, 2025. Doi: 10.1016/j.phymed.2025.157110
[9] L. Wang et al., “N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model,” International Journal of Biological Sciences, vol. 19, no. 13, pp. 4082–4102, 2023. Doi: 10.7150/ijbs.85028
[10] L. Jin et al., “Rheumatoid arthritis and COVID-19 outcomes: A systematic review and meta-analysis,” BMC Rheumatology, vol. 8, article 61, 2024. Doi: 10.1186/s41927-024-00431-5
From Natural Products to Drug Candidates: A Two-Way Research Model for Future Therapies in Cardiovascular, Arthritis, and Cancer Diseases
Over the past two decades, under the leadership of Professor Yi-Zhun Zhu, researchers at the Macau University of Science and Technology have been focusing on a distinctive bidirectional research model for small molecule drug development. This integrated strategy combines two complementary approaches: “from bioactive natural compounds to novel target identification” and “from novel therapeutic target to new small-molecule development.” Moving beyond conventional linear drug discovery processes, this framework facilitates bidirectional innovation, advancing both fundamental researches and translational applications.
Drug discovery can be conceptualized as an exploration on a vast island. Traditional approaches often follow a single linear route toward therapeutic breakthroughs, namely, the treasure. In contrast, the bidirectional model offers greater flexibility. Investigations may begin with a “coin” already in hand—such as Leonurine (SCM-198), S-Propargyl-Cysteine (SPRC), the natural compounds functioning as a valuable starting point. By studying that coin closely, researchers uncover clues about its origins, which in turn point them toward new biological targets and therapeutic directions, including NOX4, SMYD3, JMJD3, HDAC6 and so on. Alternatively, the journey begins the other way around, with a “map” in hand—a promising biological mechanism such as HDAC6/MyD88/NF-κB signaling pathway or STAT3-NAV2 axis in arthritis, serving as a guide for rational drug design. In both cases, the two pathways converge, leading to synergistic advances in drug discovery.
This strategy has yielded significant milestones, including the industrial translation of first-in-class therapeutics, and continues to drive progress across multiple therapeutic areas. In particular, the model has guided three major research trajectories: starting with leonurine, a natural product with traditional cardiovascular applications that has been advanced into modern drug development; extending into SPRC, a synthetically designed modulator of hydrogen sulfide; and progressing to epigenetic drug discovery through SMYD3 inhibition, a path with implications for vascular aging and oncology. Collectively, these directions illustrate how atural product-derived insights and target-driven design can converge within a single framework to shape the next era of medicine.
From Small molecule-to-Target: Leonurine
The journey along the “small molecule-to-target” pathway began with leonurine, a compound derived from Leonurus japonicus, a plant used in traditional medicine for cardiovascular health and gynecological diseases. What makes Leonurine significant is not only its herbal origins but also its development into a scientifically validated compound with cardioprotective effects, anti-inflammatory properties, pro-angiogenic effects following cardiac injury, and potential applications beyond cardiovascular disease which accounts for 17.9 million annual deaths globally [1] [2,3]. Beyond cardiovascular applications, it has demonstrated efficacy in mitigating endometriosis via modulation of estrogen-mediated immune dysfunction [4], as well as anti-atherosclerotic and hepatoprotective activities [5,6]. The team has also advanced Leonurine into novel formulations, the team developed a sustained-release leonurine formulation using PLGA microspheres encapsulating drug nanocrystals (Leo-nano@MP), which significantly improved lipid metabolism and reduced dosing frequency via subcutaneous administration in a hyperlipidemic rat model, demonstrating high drug loading, prolonged release, and good biocompatibility [7].
This pathway exemplifies how a single bioactive natural product can unravel novel mechanisms and open new therapeutic avenues. Leonurine thus serves as a prototype for transforming traditional herbal compounds into first-in-class therapeutics with validated mechanisms of action.
The translational development of Leonurine is supported by multiple patents from Professor Zhu’s group, covering pharmaceutical formulations and delivery technologies. For example, these include nanoliposome and microsphere systems that enhance bioavailability and enable controlled release, broadening the therapeutic window for cardiovascular and inflammatory diseases. Their patents also highlight leonurine’s role in modulating lipid metabolism, PPARγ pathways, and its use in treating liver disease and inflammation-related disorders. Collectively, these innovations elevate Leonurine from a traditional herbal compound into a modern, patent-protected therapeutic entity with substantial clinical potential.
From Small molecule-to-Target: another example, SPRC and CSE
If Leonurine represents the journey from monomer to target, S-Propargyl-Cysteine (SPRC) illustrates the complementary path—from target to molecule. Here, the therapeutic target is cystathionine Gamma Lyase (CSE), an enzyme that produces the signaling molecule hydrogen sulfide (H₂S) from L-cysteine. SPRC acts as a donor of endogenous H₂S, an endogenous gasotransmitter known for its profound effects on vascular health, inflammation, and longevity. Based on this mechanistic insight, SPRC was designed as a synthetic amino acid derivative that modulates H₂S levels.
Based on Professor Zhu’s studies, SPRC has demonstrated wide-ranging benefits: regulating immune responses, protecting neurons after stroke, and promoting angiogenesis [8,9]. In rheumatoid arthritis (RA), which affects over 18 million people globally [10], SPRC has been shown to rebalance immune cells by inhibiting the JAK/STAT pathway, reducing inflammation and slowing joint damage [11]. Beyond exploring the pharmacological efficacy of SPRC, the team have also engineered SPRC-based nanocarriers and hybrid molecules for precision therapies against RA,
This small molecule-to-target pathway highlights how identifying a novel biological mechanism—in this case, CSE as the target of SPRC—can inspire the rational design of first-in-class therapeutic candidates with translational potential.
Patents filed by Professor Zhu and his team surrounding SPRC and related signaling pathways demonstrate the translational depth of this pathway by engineering innovative drug delivery platforms. Microsphere and mesoporous silica formulations enhance the stability and sustained release of SPRC, improving its therapeutic precision in diseases such as rheumatoid arthritis and ischemic injury. Additionally, their patents on endogenous H₂S donors for RA treatment underscore the progression from mechanistic insight to tangible therapeutic inventions. These intellectual property advances ensure SPRC’s positioning not just as a promising molecule, but as a scalable and clinically adaptable treatment strategy.
Target-to-Molecule: SMYD3 and Epigenetic Regulation
Extending the target-driven approach further, the researchers turned their attention to the epigenetic regulator SMYD3, a histone methyltransferase linked to vascular aging, cellular remodeling, and cancer progression. Unlike Leonurine’s herbal origins, SMYD3 inhibition begins firmly at the target level, with the goal of designing molecules that disrupt pathogenic gene regulation.
Professor Zhu’s research team showed that, through high-throughput screening and structure-based drug design, small molecules such as ZYZ384 were identified to reduce cancer cell proliferation by lowering H3K4 trimethylation on oncogenic promoters. In models of hepatocellular carcinoma, SMYD3 inhibition suppressed tumor growth, offering a new precision epigenetic strategy against cancer [14]. Beyond oncology, targeting SMYD3 also addresses vascular senescence, the progressive aging of blood vessels that underlies hypertension, atherosclerosis, and stroke [15,16].
This work demonstrates how the target-to-molecule pathway can move beyond classical signaling molecules into the realm of epigenetics, opening entirely new frontiers for precision therapies in both cancer and age-related vascular disease.
The translational impact of SMYD3 research is evidenced by patents from Professor Zhu’s team covering novel SMYD3 inhibitors and their use in treating cancer and vascular disorders. These patents protect chemical entities capable of selectively modulating histone methylation, establishing a foundation for first-in-class epigenetic therapeutics in oncology and cardiovascular medicine.
The Bidirectional Model: Advancing Integrated Drug Discovery
Together, these approaches illustrate a cycle of discovery that moves beyond the conventional linear model of drug development. By leveraging natural products for target deconvolution and employing target-based rational design for new chemical entities, this bidirectional framework bridges traditional knowledge and contemporary science, integrating basic research with clinical translation. This model provides a robust and efficient strategy for developing small-molecule therapies that address major unmet medical needs in cardiovascular disease, arthritis, and cancer.
*Notes: This article provides research teasers for each reference to showcase the novelties
List of Patents
Preparation Method and Application of Leonurine Sustained-Release Microspheres
Preparation Method and Application of a Small-Molecule Inhibitor of Histone Methyltransferase SMYD3
Preparation Method of SCM198 Gel for Treating Skin Injuries
Microsphere Formulation Loaded with S-Propargyl-Cysteine and Its Preparation Method
Mesoporous Silica Formulation Loaded with S-Propargyl-Cysteine and Its Preparation Method
Endogenous Hydrogen Sulfide Sustained-Release Formulation: Preparation Method and Application
References
[1] https://www.who.int/health-topics/cardiovascular-diseases
[2] S. Luo, S. Xu, J. Liu, F. Ma, and Y. Z. Zhu, “Design and synthesis of novel SCM-198 analogs as cardioprotective agents: Structure-activity relationship studies and biological evaluations,” European Journal of Medicinal Chemistry, vol. 200, p. 112469, Aug. 2020, doi: 10.1016/j.ejmech.2020.112469.
[3] Z. Song, K. Song, Y. Xiao, H. Guo, Y. Zhu, and X. Wang, “Biologically Responsive Nanosystems Targeting Cardiovascular Diseases,” CDD, vol. 18, no. 7, pp. 892–913, Aug. 2021, doi: 10.2174/1567201818666210127093743.
[4] Y. Li et al., “Scm-198 alleviates endometriosis by suppressing estrogen-erα mediated differentiation and function of cd4+ cd25+ regulatory t cells,” Int. J. Biol. Sci., vol. 18, no. 5, pp. 1961–1973, 2022, doi: 10.7150/ijbs.68224.
[5] Y.-Y. Qiu, J. Zhang, F.-Y. Zeng, and Y. Z. Zhu, “Roles of the peroxisome proliferator-activated receptors (Ppars) in the pathogenesis of nonalcoholic fatty liver disease (Nafld),” Pharmacological Research, vol. 192, p. 106786, Jun. 2023, doi: 10.1016/j.phrs.2023.106786.
[6] M. Huang et al., “The multifaceted anti-atherosclerotic properties of herbal flavonoids: A comprehensive review,” Pharmacological Research, vol. 211, p. 107551, Jan. 2025, doi: 10.1016/j.phrs.2024.107551.
[7] Song Z, Meng S, Tang Z, Yang X, He Y, Zheng Y, Guo H, Du M, Zhu Y, Wang X. Injectable leonurine nanocrystal-loaded microspheres for long-term hyperlipidemia management. Biomater Sci. 2023 Jun 27;11(13):4713-4726. doi: 10.1039/d3bm00211j.
[8] S. Liu et al., “Endogenous hydrogen sulfide regulates histone demethylase JMJD3-mediated inflammatory response in LPS-stimulated macrophages and in a mouse model of LPS-induced septic shock,” Biochemical Pharmacology, vol. 149, pp. 153–162, Mar. 2018, doi: 10.1016/j.bcp.2017.10.010.
[9] Y. Xiong et al., “ZYZ-803, a novel hydrogen sulfide-nitric oxide conjugated donor, promotes angiogenesis via cross-talk between STAT3 and CaMKII,” Acta Pharmacol Sin, vol. 41, no. 2, pp. 218–228, Feb. 2020, doi: 10.1038/s41401-019-0255-3.
[10] https://www.who.int/news-room/fact-sheets/detail/rheumatoid-arthritis
[11] W. Cai et al., “S-propargyl-cysteine attenuates temporomandibular joint osteoarthritis by regulating macrophage polarization via Inhibition of JAK/STAT signaling,” Mol Med, vol. 31, no. 1, p. 128, Apr. 2025, doi: 10.1186/s10020-025-01186-6.
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[13] Z. Tang et al., “Neutrophil‐Mimetic, ROS Responsive, and Oxygen Generating Nanovesicles for Targeted Interventions of Refractory Rheumatoid Arthritis,” Small, vol. 20, no. 20, p. 2307379, May 2024, doi: 10.1002/smll.202307379.
[14] Q. Ding et al., “A novel small molecule ZYZ384 targeting SMYD3 for hepatocellular carcinoma via reducing H3K4 trimethylation of the Rac1 promoter,” MedComm, vol. 5, no. 10, p. e711, Oct. 2024, doi: 10.1002/mco2.711.
[15] Q. Ding, C. Shao, P. Rose, and Y. Z. Zhu, “Epigenetics and Vascular Senescence–Potential New Therapeutic Targets?,” Front. Pharmacol., vol. 11, p. 535395, Sep. 2020, doi: 10.3389/fphar.2020.535395.
[16] Z. Lin et al., “Discovery of deoxyandrographolide and its novel effect on vascular senescence by targeting HDAC1,” MedComm, vol. 4, no. 5, p. e338, Oct. 2023, doi: 10.1002/mco2.338.
