From Monomers to Molecules: A Two-Way Research Model Improving the Future of Cardiovascular, Arthritis, and Cancer Treatments
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 Lab to Life: The Studies Redefining tRNAs
What makes this new wave of research exciting is how it upends long-standing assumptions. Scientists once dismissed plant RNAs as irrelevant, but recent advances have proven the opposite. A significant extraction technology, known as the PARI method, has finally made it possible to extract RNA from polysaccharide-rich plants, such as ginseng, in kilogram quantities at a cost more than 90% lower than previous methods [1]. With technical hurdles removed, researchers could at last investigate tRNAs systematically.
Led by Professor Jiang, these investigations delivered profound results. A fragment from ginseng tRNA showed it could protect heart tissue from ischemia/reperfusion injury—essentially the damage caused when blood flow returns after a heart attack. In lab tests, this fragment worked over 500 times more effectively than metoprolol, a frontline medication for the heart [2]. From the Chinese yew, the same tree family that gave the world Taxol, scientists isolated a tRNA fragment capable of silencing the TRPA1 gene and stopping ovarian cancer growth [3]. Non-pathogenic strains of E. coli, long thought harmless background players in the gut, revealed tRNA fragments that kill colorectal cancer cells at nanomolar potency levels. One such fragment, EC83, proved especially powerful, offering a novel approach to designing cancer therapies [4,5]. Even Ganoderma, the “immortal mushroom” revered in traditional medicine, yielded tRNA fragments with broad anti-cancer effects, fine-tuned by subtle chemical modifications [6].
Furthermore, a tRNA fragment from Chinese yew, known as tRF-T36, was shown to target an oncogene called NUCKS1 directly. Long considered “undruggable,” NUCKS1 is overexpressed in colorectal tumors and helps drive cancer progression. By binding to NUCKS1’s genetic message, tRF-T36 shut the gene down, cutting off cancer’s fuel supply and positioning itself as a first-in-class candidate for colorectal cancer therapy [7]. Taken together, these findings transform tRNAs from overlooked molecules into a completely new drug arsenal.
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 arthritis, the team have also engineered SPRC-based nanocarriers and hybrid molecules for precision therapies against RA and melanoma [12,13,14].
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 [15]. Beyond oncology, targeting SMYD3 also addresses vascular senescence, the progressive aging of blood vessels that underlies hypertension, atherosclerosis, and stroke [16,17].
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.
[12] Q. Ding et al., “Signaling pathways in rheumatoid arthritis: implications for targeted therapy,” Sig Transduct Target Ther, vol. 8, no. 1, p. 68, Feb. 2023, doi: 10.1038/s41392-023-01331-9.
[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] X. Huang et al., “IL-2-loaded liposomes modified with sorafenib derivative exert a synergistic anti-melanoma effect via improving tumor immune microenvironment and enhancing antiangiogenic activity,” Asian Journal of Pharmaceutical Sciences, vol. 20, no. 2, p. 101020, Apr. 2025, doi: 10.1016/j.ajps.2025.101020.
[15] 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.
[16] 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.
[17] 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.
Medicinal Plant tRNAs: From Hidden Sequences to Patented RNA Drugs for Cancer and Heart Disease
Transfer RNAs (tRNAs) were thought of as the cellular equivalent of backstage crew members. They were necessary for translating the genetic code into proteins, but hardly exciting enough to be stars in their own right. As research surged into DNA, proteins, and later small-molecule drugs, tRNAs sat humbly in the background, overlooked and underestimated. That picture has now changed dramatically. tRNAs and their fragments are emerging as potent therapeutic agents. They are being reimagined as real drug candidates for some of the world’s deadliest diseases, from colorectal cancer to heart disease.
Driving this shift is a growing body of pioneering studies, including important work by Professor Zhi-Hong Jiang and his team at the Macau University of Science and Technology (MUST). Their work has developed tRNAs from overlooked molecules into viable candidates for patented RNA-based drugs, bridging modern molecular science with the ancient foundations of traditional Chinese medicine.
Why tRNAs Stayed Hidden in Plain Sight
In the early years of RNA therapeutics, siRNAs captured most attention for their ability to silence disease-causing genes with high specificity. Yet they depended on prior knowledge of genetic targets, which limited their reach in complex or poorly understood diseases. Meanwhile, research into traditional Chinese medicine (TCM) focused almost entirely on its small molecules (such as ginsenosides from ginseng or paclitaxel from yew) while overlooking the vast RNA content in these plants. The assumption was that plant RNAs would be too unstable to survive digestion or enter human cells.
This neglect meant that an abundant natural library went untapped. Every medicinal plant carries tens of thousands of RNA sequences, with tRNAs and their fragments among the most plentiful. These molecules resemble siRNAs structurally and share their gene-regulating capacity, suggesting therapeutic potential that went unnoticed for decades.
From Lab to Life: The Studies Redefining tRNAs
What makes this new wave of research exciting is how it upends long-standing assumptions. Scientists once dismissed plant RNAs as irrelevant, but recent advances have proven the opposite. A significant extraction technology, known as the PARI method, has finally made it possible to extract RNA from polysaccharide-rich plants, such as ginseng, in kilogram quantities at a cost more than 90% lower than previous methods [1]. With technical hurdles removed, researchers could at last investigate tRNAs systematically.
Led by Professor Jiang, these investigations delivered profound results. A fragment from ginseng tRNA showed it could protect heart tissue from ischemia/reperfusion injury—essentially the damage caused when blood flow returns after a heart attack. In lab tests, this fragment worked over 500 times more effectively than metoprolol, a frontline medication for the heart [2]. From the Chinese yew, the same tree family that gave the world Taxol, scientists isolated a tRNA fragment capable of silencing the TRPA1 gene and stopping ovarian cancer growth [3]. Non-pathogenic strains of E. coli, long thought harmless background players in the gut, revealed tRNA fragments that kill colorectal cancer cells at nanomolar potency levels. One such fragment, EC83, proved especially powerful, offering a novel approach to designing cancer therapies [4,5]. Even Ganoderma, the “immortal mushroom” revered in traditional medicine, yielded tRNA fragments with broad anti-cancer effects, fine-tuned by subtle chemical modifications [6].
Furthermore, a tRNA fragment from Chinese yew, known as tRF-T36, was shown to target an oncogene called NUCKS1 directly. Long considered “undruggable,” NUCKS1 is overexpressed in colorectal tumors and helps drive cancer progression. By binding to NUCKS1’s genetic message, tRF-T36 shut the gene down, cutting off cancer’s fuel supply and positioning itself as a first-in-class candidate for colorectal cancer therapy [7]. Taken together, these findings transform tRNAs from overlooked molecules into a completely new drug arsenal.
Impact: From Ancient Remedies to Modern RNA Drugs
By establishing RNA as a therapeutic class within TCM, this research expands the pharmacological universe beyond small molecules and polysaccharides. The approach also redefines drug discovery: instead of starting from a known genetic target, scientists can now screen natural RNA libraries for bioactivity and trace their effects back to gene pathways—an inversion of the traditional model.
The practical outcomes are already tangible. Two RNA-based candidates, one protecting the heart from ischemic injury and another suppressing ovarian cancer, have shown strong preclinical results. On the industrial side, the work has generated five internationally granted patents, now licensed to pharmaceutical companies. These transfers represent the highest-value academic technology deals in Macau’s history.
Conclusion
The journey of tRNAs is one of science’s surprising comeback stories. Once considered as molecular “helpers,” they have re-emerged as potent medicines drawn straight from nature’s pharmacy. From ginseng roots to yew trees, from the humble E. coli to the revered Ganoderma mushroom, tRNAs and their fragments are proving that overlooked molecules can yield extraordinary results. As the first patents are filed and partnerships formed, the world may soon see RNA-based drugs inspired not by synthetic design, but by the ancient remedies of traditional medicine.
*Notes: This article provides research teasers for each reference to showcase the novelties
References
[1] T. Yan, K. Hu, F. Ren, and Z. Jiang, “LC-MS/MS Profiling of Post-Transcriptional Modifications in Ginseng tRNA Purified by a Polysaccharase-Aided Extraction Method,” Biomolecules, vol. 10, no. 4, p. 621, Apr. 2020, doi: 10.3390/biom10040621.
[2] K. Hu et al., “A tRNA-derived fragment of ginseng protects heart against ischemia/reperfusion injury via targeting the lncRNA MIAT/VEGFA pathway,” Molecular Therapy – Nucleic Acids, vol. 29, pp. 672–688, Sep. 2022, doi: 10.1016/j.omtn.2022.08.014.
[3] K.-Y. Cao et al., “A tRNA-derived fragment from Chinese yew suppresses ovarian cancer growth via targeting TRPA1,” Molecular Therapy Nucleic Acids, vol. 27, pp. 718–732, Mar. 2022, doi: 10.1016/j.omtn.2021.12.037.
[4] K.-Y. Cao, Y. Pan, T.-M. Yan, and Z.-H. Jiang, “Purification, characterization and cytotoxic activities of individual tRNAs from Escherichia coli,” International Journal of Biological Macromolecules, vol. 142, pp. 355–365, Jan. 2020, doi: 10.1016/j.ijbiomac.2019.09.106.
[5] K.-Y. Cao, Y. Pan, T.-M. Yan, P. Tao, Y. Xiao, and Z.-H. Jiang, “Antitumor Activities of tRNA-Derived Fragments and tRNA Halves from Non-pathogenic Escherichia coli Strains on Colorectal Cancer and Their Structure-Activity Relationship,” mSystems, vol. 7, no. 2, pp. e00164-22, Apr. 2022, doi: 10.1128/msystems.00164-22.
[6] F. Ren et al., “The role of post-transcriptional modification on a new tRNAIle(GAU) identified from Ganoderma lucidum in its fragments’ cytotoxicity on cancer cells,” International Journal of Biological Macromolecules, vol. 229, pp. 885–895, Feb. 2023, doi: 10.1016/j.ijbiomac.2022.12.327.
[7] K.-Y. Cao et al., “Targeting NUCKS1 with a fragment of tRNAAsn(GUU) of Chinese yew for the treatment of colorectal cancer,” Non-coding RNA Research, vol. 11, pp. 38–47, Apr. 2025, doi: 10.1016/j.ncrna.2024.11.002.