Medicinal Plant Research 2025, Vol.15, No.5 http://hortherbpublisher.com/index.php/mpr © 2025 HortHerb Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved.
Medicinal Plant Research 2025, Vol.15, No.5 http://hortherbpublisher.com/index.php/mpr © 2025 HortHerb Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Publisher HortHerb Publisher Editedby Editorial Team of Medicinal Plant Research Email: edit@mpr.hortherbpublisher.com Website: http://hortherbpublisher.com/index.php/mpr Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada Medicinal Plant Research (ISSN 1927-6508) is an open access, peer reviewed journal published online by HortHerb Publisher. The journal publishes all the latest and outstanding research articles, letters and reviews in all aspects of medicinal plant research, including plant growth and development, plant biology, plant nutrition, medicinal properties, phytochemical constituents, fitoterapia, pharmacognosy, essential oils, ethno- pharmacology agronomic management, and phytomedicine, as well as chemistry, pharmacology and use of medicinal plants and their derivatives. HortHerb Publisher is an international Open Access publisher specializing in horticulture, herbal sciences, and tea-related research registered at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. All the articles published in Medicinal Plant Research are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. HortHerb Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
Medicinal Plant Research (online), 2025, Vol. 15, No.5 ISSN 1927-6508 http://hortherbpublisher.com/index.php/mpr © 2025 HortHerb Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Biosynthetic Pathways of Ginsenosides and Polysaccharides in Panax ginseng Yudie Wang, Meifang Li Medicinal Plant Research, 2025, Vol. 15, No. 5, 197-205 Analysis of the Metabolic Pathways of Active Compounds in Leonurus japonicus from a Genomic Perspective Yufen Wang, Ze Huang Medicinal Plant Research, 2025, Vol. 15, No. 5, 206-213 Multi-Target Pathways of Angelica sinensis in Cardiovascular and Cerebrovascular Protection Linhua Zhang, Guangman Xu Medicinal Plant Research, 2025, Vol. 15, No. 5, 214-223 Systematic Review of Clinical Applications of Astragalus membranaceus in Respiratory Disorders Yuhong Huang, Minghui Huang Medicinal Plant Research, 2025, Vol. 15, No. 5, 224-232 Protective Mechanisms of Salvia miltiorrhiza Extracts in Ischemic Heart Disease Models Jie Huang, Chuchu Liu Medicinal Plant Research, 2025, Vol. 15, No. 5, 233-243
Medicinal Plant Research 2025, Vol.15, No.5, 197-205 http://hortherbpublisher.com/index.php/mpr 197 Systematic Review Open Access Biosynthetic Pathways of Ginsenosides and Polysaccharides inPanax ginseng YudieWang1, Meifang Li 2 1 Traditional Chinese Medicine Research Center, Cuixi Academy of Biotechnology, Zhuji, 311800, Zhejiang, China 2 Tropical Medicinal Plant Research Center, Hainan Institute of Tropical Agricultural Resources, Sanya, 572025, Hainan, China Corresponding author: meifang.li@cuixi.org Medicinal Plant Research, 2025, Vol.15, No.5 doi: 10.5376/mpr.2025.15.0021 Received: 20 Jun., 2025 Accepted: 31 Jul., 2025 Published: 10 Sep., 2025 Copyright © 2025 Wang and Li, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Wang Y.D., and Li M.F., 2025, Biosynthetic pathways of ginsenosides and polysaccharides in Panax ginseng, Medicinal Plant Research, 15(5): 197-205 (doi: 10.5376/mpr.2025.15.0021) Abstract Ginseng (Panax ginseng C.A. Meyer), as a traditional Chinese medicinal material and an important economic crop, its main active components, ginsenosides and polysaccharides, have demonstrated pharmacological effects in terms of antioxidation, anti-inflammation, immune regulation and neuroprotection. This study systematically expounds the progress in the biosynthesis of ginsenosides and polysaccharides, including the roles of precursor substances and metabolic pathways, key rate-limiting enzymes, cytochrome P450 and glycosyltransferases in ginsenoside synthesis, as well as the regulation of polysaccharide synthetase and monosaccharide activation pathways in polysaccharide formation. The roles of transcription factors, signal transduction pathways and epigenetics in the regulation of synthetic pathways were further explored, and the applications of transcriptomics, proteomics and metabolomics in revealing key genes and metabolic networks were summarized. Synthetic biology and metabolic engineering have provided new ideas for the efficient production of saponins and polysaccharides, but there are still problems such as insufficient functional gene identification, incomplete pathway analysis, and restricted application transformation. In-depth research on the biosynthetic pathways of ginsenosides and polysaccharides is conducive to the efficient development and utilization of ginseng resources, and also provides a theoretical basis and technical support for the metabolic improvement of medicinal plants and the modernization of traditional Chinese medicine. Keywords Ginseng; Ginsenosides; Polysaccharides; Biosynthetic pathways; Multi-omics 1 Introduction Panax ginseng C.A. Meyer, a perennial herb of Araliaceae, has been used in traditional medicine in East Asia for thousands of years and is regarded as one of the most valuable plant resources. Its root, stem, and leaf contain large amounts of bioactive ingredients that are accountable for its curative effect. Apart from its medicinal purpose, ginseng has become an important economic crop with extensive application in the pharmaceutical, nutraceutical, functional foods, and cosmetic industries. The rising demand for natural health products globally has also augmented the industrial worth of ginseng, which is now a high-priority target for both research by scholars and commercial use (Ratan et al., 2020). Among the numerous secondary metabolites in ginseng, ginsenosides (triterpenoid saponins) and polysaccharides are the two major classes of pharmacologically active molecules. Ginsenosides exhibit broad spectrum of biological activities from antioxidant, anti-inflammatory, anticancer, neuroprotective, to cardioprotective activity. Ginseng polysaccharides are responsible for immunomodulation, anti-fatigue activity, metabolic control, and gut microbiota modulation. The harmonizing and sometimes complementary effect of these molecules forms the foundation of the pharmacology of ginseng's wide ranging therapeutic use (Hyun et al., 2021). Clarification of ginsenoside and polysaccharide biosynthetic pathways is central to the interpretation of the molecular and biochemical mechanism of their diversity and accumulation. Information regarding precursor supply, rate-limiting enzymes, glycosylation reactions, and transcriptional control provides a foundation for both fundamental biological research and applied biotechnology. In addition, pathway elucidation allows for the identification of targets for metabolic engineering, synthetic biology, and molecular breeding, offering a means to enhance yield, quality improvement, and designing new ginseng-derived products (Mancusoand Santangelo, 2017).
Medicinal Plant Research 2025, Vol.15, No.5, 197-205 http://hortherbpublisher.com/index.php/mpr 198 This study analyzed the research progress in the biosynthetic pathways of ginsenosides and polysaccharides in recent years, summarized the role of precursor metabolic pathways, key enzymes, regulatory factors, and multi-omics methods in revealing the biosynthetic network. Meanwhile, the latest progress in synthetic biology and metabolic engineering strategies for increasing the yield of metabolites was sorted out. By integrating basic research with potential applications, this study emphasizes the significant importance of biosynthesis research in the efficient utilization of ginseng resources, industrial development, and the modernization process of traditional medicines. 2 Biosynthetic Pathways of Ginsenosides in Ginseng 2.1 Precursors and primary metabolic pathways Biosynthesis of ginsenosides is triggered by the formation of isoprenoid precursors, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), via two distinct pathways: the cytosolic mevalonate (MVA) pathway and the plastidic methylerythritol phosphate (MEP) pathway. Both these pathways participate in the biosynthesis of ginsenosides in ginseng roots, while the MEP pathway is more active in leaves. Specifically, the IspD enzyme was identified as a candidate rate-limiting step of the MEP pathway, and its expression level was correlated with ginsenoside accumulation in different tissues (Xue et al., 2019; Yang et al., 2020). 2.2 Key rate-limiting enzymes and their regulation Key enzymes such as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), squalene synthase (SS), squalene epoxidase (SE), and dammarenediol-II synthase (DS) are in charge of controlling the metabolic pathway toward ginsenoside biosynthesis. Environmental conditions, especially blue and red light, can strongly stimulate the expression of these genes, thereby the ginsenoside accumulation in leaves and roots (Di et al., 2023; Liu et al., 2023). Transcription factors (e.g., MYC2, GRAS) and microRNAs likewise control expression of these biosynthetic genes with developmental and environmental signals integrated (Eom and Hyun, 2025; Wang et al., 2025). 2.3 Cytochrome P450 enzymes and glycosyltransferases involved in triterpenoid saponin biosynthesis Cytochrome P450 monooxygenases (specifically the CYP716A family) introduce hydroxyl moieties onto the triterpene framework, and UDP-glycosyltransferases (UGTs) introduce sugar moieties, creating the structural diversity of ginsenosides. Some UGTs were recently identified and characterized, including UGT94 and UGT73 families, which are responsible for specific glycosylation reactions in both protopanaxadiol (PPD) type and protopanaxatriol (PPT) type ginsenosides (Hou et al., 2022; Zhang et al., 2022; Yuan et al., 2024; Yu et al., 2024). Synthetic biology advances have also enabled these pathways to be recreated in yeast to produce ginsenosides in high yields (Jiang et al., 2022; Li et al., 2022). 2.4 Tissue specificity and secondary metabolic regulation of ginsenoside biosynthesis Ginsenoside biosynthesis is strongly tissue-specific and developmentally regulated. Gene expression and ginsenoside accumulation vary among roots, leaves, and flowers, of which the most significant ginsenoside storage tissue are the roots (Xue et al., 2019; Di et al., 2023; Liu et al., 2023). Environmental factors (e.g., light quality) and hormone also control gene expression and metabolite accumulation. Transcription factors and microRNAs are also major regulators of the ginsenoside biosynthetic fine-tuning against developmental and environmental cues (Eom and Hyun, 2025; Wang et al., 2025) (Figure 1). 3 Biosynthetic Pathways of Ginseng Polysaccharides 3.1 Classification and structural characteristics of ginseng polysaccharides Ginseng polysaccharides are complex biological macromolecules composed of various monosaccharide units connected by glycosidic linkages. They are mainly classified into neutral and acidic polysaccharides, and their composition differs depending on the plant part (roots, leaves, flowers, berries) and cultivation conditions. Glucose is the predominant monosaccharide, with other sugars such as rhamnose, arabinose, galactose, galacturonic acid, and mannose present in varying proportions. Their structure, including branching patterns and uronic acid content, is directly linked to their biological activities like immunomodulation and antioxidant activities (Guo et al., 2020; Ji et al., 2020; Fang et al., 2022).
Medicinal Plant Research 2025, Vol.15, No.5, 197-205 http://hortherbpublisher.com/index.php/mpr 199 Figure 1 Correlation between physiological indicators and ginsenosides. * Significant at p≤0.05, ** significant at p≤0.01 (Adopted from Di et al., 2023) 3.2 Precursor pathways of monosaccharide activation and polysaccharide synthesis Biosynthesis of ginseng polysaccharides proceeds with the activation of monosaccharides through metabolic pathways that yield nucleotide sugars (e.g., UDP-glucose, GDP-mannose). Key enzymes such as phosphoglucomutase (PGM), glucose-6-phosphate isomerase (GPI), UTP-glucose-1-phosphate uridylyltransferase (UGP2), fructokinase (scrK), mannose-1-phosphate guanylyltransferase (GMPP), phosphomannomutase (PMM), and UDP-glucose 4-epimerase (GALE) are integral to these processes. These enzymes catalyze the conversion of primary metabolites to activated sugar donors required to synthesize polysaccharides (Fang et al., 2022). 3.3 Roles of polysaccharide synthases and glycosyltransferases in biosynthesis Polysaccharide synthases and glycosyltransferases catalyze the modification and polymerization of the sugar residues, determining the final structure and function of ginseng polysaccharides. Transcriptome analysis identified 19 candidate enzymes in the synthesis of polysaccharides among which 17 were highly correlated with polysaccharide content. The genes encoding these enzymes are regulated by transcription factors such as MYB, AP2/ERF, bZIP, and NAC that combine the biosynthetic machinery in response to developmental and environmental cues (Fang et al., 2022). 3.4 Relationship between polysaccharide biosynthesis, cell wall metabolism, and storage substances Ginseng polysaccharide biosynthesis is closely associated with cell wall metabolism since the majority of polysaccharides are structural materials or reserve substances. Roots have the highest proportion of
Medicinal Plant Research 2025, Vol.15, No.5, 197-205 http://hortherbpublisher.com/index.php/mpr 200 polysaccharides and their monosaccharide compositions, which reflects storage and structural roles. Polysaccharide biosynthesis is regulated dynamically to facilitate cell wall building and reserve carbohydrate deposition, thus enhancing plant growth, stress tolerance, and medicinal property (Guo et al., 2020). 4 Regulatory Mechanisms of Ginsenoside and Polysaccharide Biosynthesis 4.1 Roles of transcription factors in ginsenoside and polysaccharide biosynthesis Transcription factors (TFs) such as bHLH, WRKY, MYB, NAC, and GRAS are central regulators of ginsenoside and polysaccharide biosynthesis in Panax ginseng. For ginsenosides, bHLH, WRKY, MYB, and ERF TFs have been shown to directly regulate the expression of important biosynthetic genes such as those encoding cytochrome P450s and glycosyltransferases (Wei et al., 2024). For example, PgWRKY4X activates the transcription of squalene epoxidase to promote ginsenoside accumulation (Yao et al., 2020), and PgNAC72 responds to methyl jasmonate (MeJA) and regulates saponin biosynthesis by upregulating dammarenediol synthase (Jiang et al., 2024). GRAS TFs, for example, PgGRAS68-01, also modulate ginsenoside biosynthesis through spatiotemporal gene expression (Liu et al., 2023). In polysaccharide biosynthesis, MYB, AP2/ERF, bZIP, and NAC TFs are linked to the expression of key enzymes involved in sugar metabolism and polymerization, indicating their regulation on polysaccharide structure and content (Fang et al., 2022; Hou et al., 2022) (Figure 2). Figure 2 Ginsenoside biosynthesis pathway (A) and saponin skeleton biosynthesis gene expression pattern (B) (Adopted from Hou et al., 2022) 4.2 Influence of signal transduction pathways Environmental stresses, exogenous elicitors, and hormone signals are highly important for ginsenoside and polysaccharide biosynthesis. Methyl jasmonate (MeJA) is a potent elicitor, inducing TFs like NAC and MYB and initiating gene activation in the ginsenoside pathway (Zhang et al., 2021; Jiang et al., 2024). Sucrose is a metabolic signal, inducing ginsenoside biosynthesis by promoting glycolysis and the mevalonate pathway, particularly by activating HMGR (Rui et al., 2022). Environmental elicitors such as fungal elicitors (e.g., Chaetomium globosum) and cerium ions also enhance ginsenoside accumulation by initiating ROS signaling and endogenous MeJA biosynthesis (Yao et al., 2020; Zhang et al., 2021). WRKY TFs also respond to various abiotic stresses (heat, cold, drought), associating stress adaptation with the generation of secondary metabolites (Di et al.,
Medicinal Plant Research 2025, Vol.15, No.5, 197-205 http://hortherbpublisher.com/index.php/mpr 201 2021). In polysaccharides, similar regulatory networks with hormone- and stress-inducible TFs direct biosynthetic gene expression (Fang et al., 2022). 4.3 Epigenetic regulation Epigenetic pathways, particularly non-coding RNAs such as microRNAs (miRNAs), are also emerging as important regulators of ginsenoside biosynthesis. miRNAs can target and silence key biosynthetic genes, such as dammarenediol synthase and protopanaxatriol synthase, by regulating triterpenoid biosynthesis (Wei et al., 2024; Eom and Hyun, 2025). Although DNA methylation and histone modification research in ginseng is still limited, these epigenetic changes will definitely influence the chromatin state and transcriptional activity of biosynthetic genes. The integration of multi-omics approaches and genome editing technologies will keep revealing the active epigenetic regulation of ginsenoside and polysaccharide biosynthesis (Eom and Hyun, 2025). 5 Application of Multi-Omics in Biosynthetic Pathway Studies 5.1 Transcriptomics revealing key gene expression patterns Transcriptome analyses, including bulk and single-cell RNA sequencing, have made possible the discovery of genes and gene clusters involved in ginsenoside and polysaccharide biosynthesis. Coexpression network analysis associates gene expression profiles with specific biosynthetic steps, showing tissue-specific and developmental regulation of pathway genes. Time-series transcriptomics also enables determination of regulatory genes and dynamic variation upon environmental or developmental cues (Singh et al., 2022; Wang et al., 2024). 5.2 Proteomics in metabolic pathway elucidation Proteomics complements transcriptomics by confirming the presence, abundance, and post-translational modifications of enzymes in biosynthetic pathways. Quantitative proteomic profiling is used for the validation of candidate genes, the discovery of enzyme complexes, and the determination of the functional organization of metabolic networks. Integration with transcriptomic data enhances the accuracy of pathway reconstruction and functional annotation (Yang et al., 2021). 5.3 Metabolomics for tracing accumulation patterns of secondary metabolites in ginseng Metabolomics quantifies ginsenosides, polysaccharides, and intermediates directly, enabling the monitoring of metabolite accumulation in various tissues, developmental stages, and environmental conditions. The alignment of metabolite profiles with gene and protein expression datasets enables the identification of regulatory bottlenecks and key nodes in biosynthetic pathways (Singh et al., 2022). 5.4 Multi-omics integration and construction of regulatory network models Integrative multi-omics strategies combine transcriptomic, proteomic, and metabolomic data to construct large-scale models of gene-protein-metabolite interactions and regulatory modules. These models give insight into pathway behavior under varying conditions, identify regulatory modules, and enable predictions regarding gene-protein-metabolite interaction networks (GPMN). Advanced computational capabilities and unsupervised integration techniques such as correlation-based network analysis and machine learning facilitate the discovery of novel pathway components and regulatory interactions, giving a global view of specialized metabolism in ginseng (Singh et al., 2022; Wieder et al., 2024). 6 Advances in Synthetic Biology and Metabolic Engineering 6.1 Establishment of microbial heterologous expression systems Microbial hosts such as Saccharomyces cerevisiae (yeast) and Escherichia coli have also been genetically modified to express plant biosynthetic pathways, whereby complex isoprenoids and ginsenosides are synthesized. These systems are blessed with well-characterized genetics, ease of manipulation, and scalable fermentations and therefore most appropriate for industrial application. Non-conventional yeasts and bacteria are also being explored because they are metabolically flexible and capable of utilizing various substrates (Navale et al., 2021; Patra et al., 2021).
Medicinal Plant Research 2025, Vol.15, No.5, 197-205 http://hortherbpublisher.com/index.php/mpr 202 6.2 Optimization of metabolic pathways and strategies for high-yield synthesis Optimization techniques are modular pathway design, metabolic flux balance, and dynamic control systems. SynBio tools support the reconstruction of multi-gene pathways across various species, and computational modeling and machine learning guide pathway design and predict bottlenecks. Techniques such as chromosomal integration, enzyme engineering, and compartmentalization further optimize yield and stability (Lee et al., 2018; Choi et al., 2019; García-Granados et al., 2019). 6.3 Application of CRISPR/Cas gene editing in pathway regulation CRISPR/Cas systems have revolutionized metabolic engineering with the potential to introduce precise, multiplexed genome modifications. CRISPR/Cas9 is used in bacteria and yeast for specific gene knockouts, pathway streamlining, and insertion of large biosynthetic gene clusters (Patra et al., 2021; Lv et al., 2022). This not only accelerates strain development but also allows gene expression fine-tuning for improved metabolite yields. 6.4 Industrial synthesis: prospects and challenges Industrial production of ginsenosides is constrained by metabolic load, pathway bottlenecks, and demand for robust, high-yielding strains. These limitations are being overcome by recent advances in systems metabolic engineering, genome-scale modeling, and high cell-density fermentation. Better genetic stability, scalability of process, and cost-effectiveness are yet required for industrial applications on a large scale (Navale et al., 2021; Han et al., 2023). 7 Current Research Status and Limitations 7.1 Unresolved aspects in pathway elucidation While significant progress has been achieved in the identification of key enzymes and intermediates of ginsenoside and polysaccharide biosynthesis, several important points remain unresolved. For ginsenosides, for example, the complete set of cytochrome P450s responsible for specific hydroxylation and oxidation reactions is yet to be completely delineated, and tissue- and development stage-specific accumulation patterns are not clearly understood. Similarly, for ginseng polysaccharides, the precise mechanisms of polymerization, modes of branching, and their regulation by upstream sugar nucleotide pools must be clarified. Limited data on subcellular localization and metabolite transport also hinders a thorough understanding of biosynthetic fluxes (Velte and Stawinoga, 2016). 7.2 Insufficient systematic identification of functional genes and enzymes Although transcriptomic and proteomic studies provided numerous candidate genes, there is no comprehensive functionally validated set of enzymes and regulator proteins. Many predicted genes are uncharacterized due to heterologous expression difficulties, redundancy among enzyme family members, or very low in planta expression. Moreover, only on the rarest of occasions have been transcription factors and post-translational modifiers that regulate pathway activity identified, precluding systematic reconstruction of the regulatory network (Yousef, 2023). 7.3 Bottlenecks in translating basic research into applied outcomes Translational applications, for instance, metabolic engineering, synthetic biology, large-scale production of high-value ginsenosides or polysaccharides, are presently still limited by incomplete pathway information. Low efficiency of heterologous expression systems, low pathway flux, uncontrolled stereochemistry, and the inability to reproduce tissue-specific or developmental regulation ex vivo are present bottlenecks. In addition, integration of multi-omics information into predictive models to optimize cultivation or bioengineer is in its infancy. Filling these gaps is required in order to move towards precision-guided manufacturing and industrial utilization (Shin, 2023). 8 Concluding Remarks There have been significant developments in recent years toward elucidating the Panax ginseng biosynthetic pathways of ginsenosides and polysaccharides. These include the identification and functional characterization of
Medicinal Plant Research 2025, Vol.15, No.5, 197-205 http://hortherbpublisher.com/index.php/mpr 203 ginsenoside formation rate-limiting enzymes, cytochrome P450s, and glycosyltransferases, and polysaccharide synthases and the precursor activation pathways for polysaccharide synthesis. Multidisciplinary omics approaches, including transcriptomics, proteomics, and metabolomics, provided new insights into tissue-specific profiles of accumulation, regulatory networks, and environmental or developmental control of metabolite biosynthesis. The combined results have complemented our understanding of the molecular process underlying the generation and complexity of ginseng bioactive compounds. Understanding of ginsenoside and polysaccharide biosynthetic pathways has direct applications in the development and sustainable utilization of ginseng resources. Discovery of key genes, enzymes, and regulatory systems allows for specific metabolic engineering, uses of synthetic biology, and molecular breeding programs to enhance the yield and quality of metabolites. Furthermore, knowledge from pathway studies guides the standardization of ginseng products to give reproducible quality, efficacy, and safety for both traditional medicine and commercial purposes. Future research will likely focus on integrating multi-omics information to develop precise regulatory networks for ginsenoside and polysaccharide biosynthesis. Genome editing, CRISPR/Cas-directed pathway remodeling, and synthetic biology promise much for the targeted overexpression of active metabolites. Sustainable industrialization strategies like bioreactor-based production and optimized cultivation practices will also be crucial to meet global demand while preserving natural ginseng resources. In total, long-term interdisciplinary research will drive both fundamental knowledge and practical applications, bridging the divide between ginseng biosynthetic research and industrial and therapeutic uses. Acknowledgments The authors sincerely thank the research team for their full assistance during the course of the study and their strong support in the compilation of relevant materials. They also extend heartfelt gratitude to the two anonymous reviewers, whose constructive suggestions provided valuable guidance for further improving this manuscript Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Choi K., Jang W., Yang D., Cho J., Park D., and Lee S., 2019, Systems metabolic engineering strategies: integrating systems and synthetic biology with metabolic engineering, Trends Biotechnol, 37(8): 817-837. https://doi.org/10.1016/j.tibtech.2019.01.003 Di P., Sun Z., Cheng L., Han M., Yang L., and Yang L., 2023, LED light irradiations differentially affect the physiological characteristics, ginsenoside content, and expressions of ginsenoside biosynthetic pathway genes in Panax ginseng, Agriculture, 13(4): 807. https://doi.org/10.3390/agriculture13040807 Di P., Wang P., Yan M., Han P., Huang X., Yin L., Yan Y., Xu Y., and Wang Y., 2021, Genome-wide characterization and analysis of WRKY transcription factors in Panax ginseng, BMC Genomics, 22: 317. https://doi.org/10.1186/s12864-021-08145-5 Eom S., and Hyun T., 2025, MicroRNA-mediated regulation of ginsenoside biosynthesis in Panax ginseng and its biotechnological implications, Sci. Prog., 108(1): 00368504251332109. https://doi.org/10.1177/00368504251332109 Fang X., Wang H., Zhou X., Zhang J., and Xiao H., 2022, Transcriptome reveals insights into biosynthesis of ginseng polysaccharides, BMC Plant Biol., 22: 326. https://doi.org/10.1186/s12870-022-03995-x García-Granados R., Lerma-Escalera J., and Morones-Ramírez J., 2019, Metabolic engineering and synthetic biology: synergies, future, and challenges, Front. Bioeng. Biotechnol., 7: 36. https://doi.org/10.3389/fbioe.2019.00036 Guo M., Shao S., Wang D., Zhao D., and Wang M., 2020, Recent progress in polysaccharides from Panax ginseng C. A. Meyer, Food Funct., 11(12): 10386-10402. https://doi.org/10.1039/d0fo01896a Han T., Nazarbekov A., Zou X., and Lee S., 2023, Recent advances in systems metabolic engineering, Curr. Opin. Biotechnol., 84: 103004. https://doi.org/10.1016/j.copbio.2023.103004
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Medicinal Plant Research 2025, Vol.15, No.5, 206-213 http://hortherbpublisher.com/index.php/mpr 206 Research Insight Open Access Analysis of the Metabolic Pathways of Active Compounds inLeonurus japonicus from a Genomic Perspective Yufen Wang, Ze Huang Traditional Chinese Medicine Research Center, Cuixi Academy of Biotechnology, Zhuji, 311800, Zhejiang, China Corresponding author: ze.huang@cuixi.org Medicinal Plant Research, 2025, Vol.15, No.5 doi: 10.5376/mpr.2025.15.0022 Received: 26 Jun., 2025 Accepted: 08 Aug., 2025 Published: 17 Sep., 2025 Copyright © 2025 Wang and Huang, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Wang Y.F., and Huang Z., 2025, Analysis of the metabolic pathways of active compounds in Leonurus japonicus from a genomic perspective, Medicinal Plant Research, 15(5): 206-213 (doi: 10.5376/mpr.2025.15.0022) Abstract As a traditional Chinese medicine, Leonurus japonicus contains a variety of active ingredients with anti-inflammatory and antioxidant effects. To elucidate the metabolic mechanisms of the active substances, this study, from a genomic perspective, combined transcriptomic, proteomic and metabolomic data to analyze the synthetic pathways and regulatory networks of key metabolites such as alkaloids, flavonoids and polysaccharides. Research has found that the formation of leonurine involves the expansion of key enzymes, such as ADC, UGT and SCPL, as well as specific gene clusters. Flavonoids such as luteolin regulate estrogen synthesis through the MAPK/CREB pathway. Candidate biosynthesis genes for polysaccharides have also been identified. The study also explored the prospects and challenges of synthetic biology and metabolic engineering in the industrial application of metabolites. This study provides theoretical support and technical paths for the molecular mechanism analysis, resource development and modernization of traditional Chinese medicine of the active components of Leonurus japonicus. Keywords Leonurus japonicus var. tongzi; Bioactive compounds; Metabolic pathways; Genomics; Multi-omics 1 Introduction Leonurus japonicus var. tongzi is a variant of the Leonurus genus in the Lamiaceae family, primarily distributed in Guizhou, Sichuan, and other regions of China. It exhibits notable therapeutic efficacy and strong environmental adaptability, making it an important component of local traditional medicine systems (Ou et al., 2025). As a commonly used gynecological herb, its medicinal applications can be traced back to ancient texts such as the Shennong Ben Cao Jing and the Compendium of Materia Medica, where it was traditionally prescribed for irregular menstruation, postpartum abdominal pain, and threatened miscarriage. Modern studies have further confirmed its efficacy in promoting uterine contraction, improving blood circulation, and exerting anti-inflammatory and analgesic effects (Miao et al., 2019). In addition, L. japonicus var. tongzi possesses heat-clearing, detoxifying, anti-swelling, and diuretic properties. In recent years, its potential in treating cardiovascular and cerebrovascular diseases and modulating immune function has gained increasing attention. Compared with common Leonurus japonicus, this variety shows unique characteristics and application value in terms of bioactive compound accumulation, ecological adaptability, and localized medicinal use experience. The herb contains a range of bioactive molecules, including alkaloids, flavonoids, and polysaccharides, that all contribute to confering to it therapeutic activity. These types of compounds possess anti-inflammatory, antioxidant, immunomodulatory, and vasoprotective activities that are behind its typical medicinal use. Current genomics provides robust capabilities to explore biosynthesis and regulation of active constituents of medicinal plants. Genomic approaches, combined with transcriptomics, proteomics, and metabolomics, enable systematical identification of functional genes, regulatory networks, and enzyme pathways and supply mechanistic data on biosynthesis of bioactive metabolites (Miao et al., 2019; Shi et al., 2022). This study extensively summarizes the recent developments in genomic studies of L. japonicus var. tongzi focusing on identification of biosynthetic pathways and regulation mechanism of its major bioactive metabolites. Integrating genomics with multi-omics data, it aims to yield a complete view of metabolite biosynthesis towards resource development, metabolic engineering, and rationalization of traditional Chinese medicine.
Medicinal Plant Research 2025, Vol.15, No.5, 206-213 http://hortherbpublisher.com/index.php/mpr 207 2 Genomic Research Progress of Leonurus japonicus var. tongzi 2.1 Genome sequencing and assembly status A chromosome-level genome assembly at high resolution of L. japonicus was achieved with ONT long read and Hi-C combined. The assembly length is 489.34 Mb, has ten anchored chromosomes, a scaffold N50 of 50.86 Mb, and a contig N50 of 7.27 Mb. Assembly quality is guaranteed by having a BUSCO score of 99.2%, and 22,531 protein-coding genes are annotated, which offers a solid foundation for functional and comparative genomics (Yang et al., 2022; Li et al., 2023; Wang et al., 2024) (Figure 1). Figure 1 Genomic analysis of L. japonicus and L. sibiricus. (A) Overview of the genome assemblies and annotations of L. japonicus andL. sibiricus; (B) Collinearity analysis between L. japonicus andL. sibiricus chromosomes (Adopted from Li et al., 2023) 2.2 Transcriptome analysis and functional gene identification Transcriptomic information from various tissues has allowed protein-coding gene annotation and description of significant enzymes involved in special metabolism, such as diterpenoid and alkaloid biosynthesis. Multi-omics integration revealed the roles of arginine decarboxylase (ADC), uridine diphosphate glucosyltransferase (UGT), and serine carboxypeptidase-like (SCPL) acyltransferase in leonurine biosynthesis, with geneset-specific clusters andL. japonicus regulatory networks (Wang et al., 2022; Li et al., 2023; Chen et al., 2024).
Medicinal Plant Research 2025, Vol.15, No.5, 206-213 http://hortherbpublisher.com/index.php/mpr 208 2.3 Gene family expansion and evolutionary characteristics Comparative phylogenomic analysis revealed 58 expanded gene families in L. japonicus, particularly those related to specialized metabolism, e.g., diterpenoid biosynthesis. Gene duplication and neofunctionalization events, particularly within the UGT-SCPL gene cluster, have been involved in the special accumulation of leonurine in L. japonicus compared to related taxa (Wang et al., 2024). 2.4 Comparative genomics with other medicinal plants Comparative genomic comparison of L. japonicus and L. sibiricus revealed differences in genome structure and gene content, such as biosynthetic biosynthetic pathways of leonurine. Syntenic and phylogenetic comparison with other medicinal plants and Lamiaceae family members revealed whole-genome duplication histories and evolutionary orientations of biosynthetic gene clusters underpinning the intriguing metabolic potential of L. japonicus (Yang et al., 2022; Chen et al., 2024). 3 Elucidation of Metabolic Pathways of Bioactive Components 3.1 Biosynthetic pathways and key functional enzymes of alkaloids Leonurine and stachydrine are significant alkaloids in L. japonicus. The leonurine biosynthesis was disclosed by multi-omics approaches, and arginine decarboxylase (ADC), uridine diphosphate glucosyltransferase (UGT), and serine carboxypeptidase-like (SCPL) acyltransferase were confirmed to be crucial enzymes. The UGT-SCPL gene cluster, which is developed through gene duplication and neofunctionalization, participates in leonurine accumulation in L. japonicus. Whereas the metabolic pathway of stachydrine is thoroughly explained, its anabolic (biosynthetic) pathway is inadequately reported and a subject of continued study (Li et al., 2023; He et al., 2024; Ou et al., 2025). 3.2 Biosynthesis and regulatory mechanisms of flavonoids Flavonols such as luteolin and luteolin-7-methylether are major pharmacological components of L. japonicus. They inhibit aromatase (CYP19) expression and estrogen biosynthesis by regulating the MAPK/CREB pathway. Transcriptomics analysis revealed that flavonoids regulate gene expression of estrogen biosynthesis and inflammation, which is the molecular basis of their therapeutic activities (Du et al., 2020; Shi et al., 2024). 3.3 Biosynthetic pathways of polysaccharides and their precursors Even though the complete biosynthetic routes of the polysaccharides in L. japonicus are not yet as well described as in the case of alkaloids and flavonoids, genomic resources and transcriptomics now enable identification of candidate genes for the biosynthesis of the polysaccharides. These include glycosyltransferase-coding genes and precursor sugar-producing enzyme-coding genes that are overrepresented in specialized metabolic gene families (Wang et al., 2024). 3.4 Formation and characteristics of unique or enriched metabolites L. japonicus var. tongzi is remarkable due to the accumulation of leonurine, as a consequence of neofunctionalization and gene cluster expansion of the UGT-SCPL genes. Furthermore, labdane diterpenoids and stachydrine analogues are abundant in this taxon, whose localization within glandular trichomes and quantitation in diverse plant sources were recently characterized. These new metabolites explain the plant's pharmacological profile and ecological acclimation (Xiao et al., 2017; Lee et al., 2020; Zhang et al., 2025) (Figure 2). 4 Research Strategies Integrating Genomics and Multi-omics 4.1 Transcriptomic approaches revealing expression patterns Transcriptome profiling by RNA sequencing of various tissues has enabled the identification and annotation of more than 22 000 protein-coding genes in L. japonicus. The research has provided expression profiles of significant genes, including biosynthetic genes for the specialized metabolites diterpenoids and alkaloids. For example, transcriptomics found arginine decarboxylase (ADC), uridine diphosphate glucosyltransferase (UGT), and serine carboxypeptidase-like (SCPL) acyltransferase genes are vital for biosynthesis of leonurine, and also transcription factors playing roles in ecological utilization and medicinals (Li et al., 2023; Chen et al., 2024).
Medicinal Plant Research 2025, Vol.15, No.5, 206-213 http://hortherbpublisher.com/index.php/mpr 209 Figure 2 Metabolic Pathways of Active Compounds and Pharmacological Properties of Leonurus japonicus var. Tongzi (Adopted from Lee et al., 2020) 4.2 Applications of proteomics in functional enzyme identification Proteomic methods, alongside enzyme assays, have authenticated the role of catalysts in diterpenoids' and leonurine's biosynthesis pathways. Functional analysis of diterpene synthases, for instance, has identified enzymatic reactions leading to the biosynthesis of characteristic spiro-labdane diterpenoids in L. japonicus (Li et al., 2023). 4.3 Contributions of metabolomics to studying metabolite accumulation Metabolomics, in recent years due to the potency of mass spectrometry, has made large-scale profiling of isomers and signature markers between hundreds of metabolites possible. Studies have identified unique differences in the accumulation of metabolites between plant organs, areas, and states, thus making quality control as well as resource utilization feasible (Garran et al., 2019; Zhang et al., 2025). 4.4 Multi-omics integration and metabolic regulatory network models The integration of genomics, transcriptomics, proteomics, and metabolomics made it possible to create metabolic regulatory networks. Such models indicate how enzyme activity, gene expression, and metabolite accumulation are regulated, permitting system-level understanding of biosynthesis and regulation of bioactive compounds in L. japonicus (Li et al., 2023; Wang et al., 2024). 5 Regulatory Mechanisms of Metabolism 5.1 Roles of transcription factors in metabolic pathway regulations Transcription factors such as MYB, bHLH, and WRKY have been reported to be vital in plant secondary metabolism regulation, including alkaloid, flavonoid, and terpenoid biosynthesis. In L. japonicus, from transcriptomic and multi-omics, biosynthetic gene clusters and regulatory modules for the biosynthesis of some of the major metabolites such as leonurine and stachydrine have been identified. Although direct functional
Medicinal Plant Research 2025, Vol.15, No.5, 206-213 http://hortherbpublisher.com/index.php/mpr 210 investigation on some of the MYB, bHLH, or WRKY factors in L. While functional studies in M. japonicus are in their infancy, the families play a part in the regulation of metabolic gene expression, as indicated by coordinated biosynthetic gene expression and amplification of gene clusters for specialized metabolism (Li et al., 2023; Wang et al., 2024). In addition, the MAPK signal pathway, being transcription factor-controllable, was discovered to regulate the expression of genes involved in estrogen biosynthesis and other metabolism (Du et al., 2020; Shi et al., 2024). 5.2 Signal regulation by plant hormones and environmental factors Plant hormones and the environment influence L. japonicus metabolic pathways tremendously. For example, MAPK and PI3K/AKT/NF-κB signaling pathways are involved in the modulation of estrogen biosynthesis, anti-inflammation reactions, and even wound healing, generally under hormonal or environmental stimuli (Shi et al., 2022; Ou et al., 2025). Chemical entities like luteolin and analogs influence such pathways, regulating the expression of such major metabolic enzymes and mediators. In addition, environmental stresses such as pathogen infection or oxidative stress trigger signal cascades that alter the accumulation of secondary metabolites, the sources of plant adaptability and medicinal value (Park et al., 2022; He et al., 2024). 5.3 Influence of epigenetics New findings show that epigenetic processes—DNA methylation, histone modification, and non-coding RNAs—are engaged in gene expression and metabolite accumulation regulation in medicinal plants. For L. japonicus, microRNA (miR-19a-3p) regulated apoptosis-related pathways, which influenced the anti-cancer activity of the plant through PTEN/PI3K/AKT pathway modulation (Park et al., 2022). Immediate research regarding DNA methylation and histone modification for L. is unavailable. When japonicus are not available, these mechanisms are likely to be involved in the dynamic regulation of biosynthetic gene clusters and tissue-specific bioactive compound accumulation, as observed in other medicinal crops. 6 Prospects of Synthetic Biology and Metabolic Engineering Applications 6.1 Construction and optimization of microbial heterologous expression platforms Identification of biosynthetic key genes (e.g., ADC, UGT, and SCPL for leonurine) makes reconstruction of plant metabolic pathways in microbial hosts possible. Large-scale production and functional validation of plant metabolites are possible through heterologous expression in bacteria or yeast. The use of strong microbial chassis, platform vector modularity, and genetically encoded biosensors also enhances the efficiency and precision of these platforms to produce valuable compounds in extranatural plant environments (Calero and Nikel, 2018; Li et al., 2023; Yu et al., 2023). 6.2 Application of gene editing technologies in functional gene validation and metabolic improvement CRISPR/Cas9 and other gene editing technologies are more and more being employed to validate gene function and modulate metabolic pathways. The technologies enable efficient management of biosynthetic genes, pathway regulators, and gene clusters in microbial platforms as well as even in L. japonicus itself. Multigene editing and synthetic gene circuits allow coordinated regulation of complex pathways, promoting yield and enabling the synthesis of new derivatives (Lee et al., 2018; Zhu et al., 2019; Lv et al., 2022; Kwan et al., 2023). 6.3 Pathway optimization and strategies for efficient biosynthesis Pathway optimization is to equilibrate gene expression, enzyme activity, and metabolic flux. Strategies include promoter engineering, enzyme engineering, dynamic regulation, and computational modeling for pathway performance prediction and optimization. Multigene stacking and assembly module systems can allow flexible reconstruction and fine-tuning of entire biosynthetic networks to optimize the yields of target metabolites (Zhu et al., 2019; Li et al., 2022; Lv et al., 2022; Kwan et al., 2023). 6.4 Challenges and opportunities in industrial development The main challenges include pathway elucidation incompleteness, host cell metabolic burden, and scalable, efficient production systems needed. The opportunities are the exploration of systems metabolic engineering, integration of omics data, and development of new microbial chassis for industrial bioproduction. Future advances
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