Da-Cheng Hao ^1* Yaoxuan Wang ¹ Richard Spjut ² Chunnian He ³

• ¹ Dalian Jiaotong University, Dalian, China
• ² World Botanical Associates, Bakersfield, California, United States
• ³ Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing Municipality, China

There is a Chinese saying that goes, "The most profound takes the simpliest form". The phylogenetically close taxa usually have similar phytometabolite profiles, and taxa that are closely related in chemotaxonomy often have analogous ethnopharmacological uses and display similar bioactivities. This is the simple core idea of "Pharmacophylogeny", and consequent the proposed term "Pharmacophylomics" aims to disentangle the intricate relationships and connectivity between medicinal plant phylogeny, phytochemical constituents and bioactivities/therapeutic utilities based on emerging omics data (Fig. 1) (Hao and Xiao, 2023);, such as those of genomics, transcriptomics and metabolomics data are very useful, so as to promote pharmaceutical resource discovery and plantbased drug R&D. In recent years, more phytomedicine researchers become familiar with the theory and methods of pharmacophylogeny (Moutouama and Gaoue, 2024), but the research on the simultaneous examination of phylogeny/phylogenomics, phytochemical constituentsstry, and bioactivity is still limited. Based on the 21 papers published in Volume I and II of this Research Topic (Hao et al., 2023a), the volume III furtherhas contributed eight brilliant enlightening papers on the phylogenomics, metabolomics, network pharmacology, ethnopharmacology and bioactivity of various medicinal species, covering algae (Su et al., 2024), monocot (Bencheikh et al., 2024;Luo et al., 2024), basal eudicot (Bencheikh et al., 2024;Pan et al., 2024), core eudicot (Ding et al., 2024), Lamiids (Liu et al., 2024) and Campanulids (Luo et al., 2024), etc. These research findingworks provide rich phytometabolite and bioactivity information for deeper exploration on 设置了格式: 非突出显示 pharmacophylogeny, facilitating the analysis of distribution patterns of various medicinal compounds and pharmacological activities on the phylogenetic tree (Hao et al., 2024a), the inference of biosynthetic pathways and therapeutic mechanisms of phytometabolites, and the search for alternative/complementary medicine sources.Fermentation is an important concoction processing technique for botanical drugphytomedicines, which transforms and enhances the active ingredients of herbal medicine via specific microbial processes (Luo et al., 2024), therefore shifting their pharmacological effects. FermentationThis TCM processing method may contribute additional dimension for expanding theory and application of pharmacophylogeny, as similar fermentation strains and conditions could be used in species with similar phytometabolites, and overlapping but not completely consistent chemical profiles could be generated after microbial transformation, which provide more chemical space for the use of fermented botanical drugs in areas such as anti-cancer, hypolipidemic, antioxidant, antimicrobial, cosmetologycosmetics, and intestinalgut microflora regulation. The fermentation technology reduces toxic side effects of some crude drugs, enhances drug efficacy, and creates new active ingredients, which could be especially important to the species rich and alkaloid abundant genera (Pan et al., 2024).The puzzling interaction between microbial strains and crude drugs is another intriguing topic.Managing factors affecting the microbial activities and fermentation process is vital for the successful transformation and enhancement efficacy improvement of herbal drugs. In this regard, the pharmacophylogeny approach also has its place. For example, we can assume that bacteria or fungi with close genetic relationships interact with specific plant compounds in a similar way, and thus predict the similarities and differences in the spectrum of transformation products based on the composition of the microbial community. There is too much work to be done in this area, and it is not limited to TCM species. Fermentation microbial research can be conducted on ethnomedicine species around the world, e.g., those of Africa (Bencheikh et al., 2024) and Asia (Liu et al., 2024). The molecular phylogeny and metabolomic information are essential to understand the medicinal value of each microbial/plant genus and to develop alternative medicinal resources. They are also applicable in food medicine continuum (FMC) plants, which are extensively distributed in worldwide ethnomedicine. Pharmacophylogeny is very useful in expanding FMC and medicinal plant resources (Hao and Xiao, 2023), authentication/quality control of herbal medicines, predicting the chemicals or bioactive constituents of herbals and identification/quantification of chemicals. Reports on 设置了格式: 非突出显示 phytometabolites and pharmacological properties of algae (Su et al., 2024), regarded as lower plants, are relatively few, despite the presence of many types of vascular plant metabolites therein, e.g., coumarins and diterpenes. In the coming years, pharmacophylogeny and pharmacophylomics could be more powerful in mining natural products from taxa of various evolutionary levels (Lu and Tang, 2020), refining ethnopharmacology understandings, therefore advancing the sustainable conservation and consumption of natural pharmaceutical resources.The global medicinal plant diversity is threated by the increasingly intense anthropogenic activities, while phrmacophylogeny and pharmacophylomics help sustainable conservation and utilization of precious phytomedicine resources. Based on the harvest of first two volumes, the volume III (https://www.frontiersin.org/research-topics/62190/plant-metabolites-in-drug-discovery-the-prismperspective-between-plant-phylogeny-chemical-composition-and-medicinal-efficacy-volume-iii) strives to gain a deeper understanding of phylogeny/evolution, phytometabolites and polypharmacology of genera/families of interest. We always advocate to conduct such investigations within the context of pharmacophylogeny and pharmacophylomics, and we are happy to publish such comprehensive work in this volume. The Lamiaceae genus Dracocephalum, with more than 30 species, possesses diverse medicinal activities and is traditionally used in Eurasian ethnomedicine (Liu et al., 2024). The geographical distribution, metabolite identification, and bioactivity of Dracocephalum species were extensively investigated, but there are debates on the taxonomy of Dracocephalum and closely related genera Hyssopus and Lallemantia, which presents an opportunity for pharmacophylogenetic studies of these medicinal taxa. Liu et al. ( 2024) present a multidimensional view of the geographical distribution, phylogenetics, phytometabolites and chemodiversity, ethnopharmacological uses, and pharmacology of Dracocephalum, Hyssopus, and Lallemantia. These genera were concentrated in Europe, with species adapted to diverse climates.They showed close phylogenetic relationships, with Dracocephalum and Hyssopus displaying intertwined patterns on the phylogenetic tree. among more than 900 reported phytometabolites of three genera, terpenoids and flavonoids are the most abundant. The newly identified novel metabolites of Dracocephalum expand chemical space to be bioprospected. Ethnopharmacologically, these three genera are especially useful in treating respiratory, liver and gall bladder diseases. Phytometabolites of these genera have various bioactivities such as hepatoprotective, anti-inflammation, antimicrobial action, anti-hyperlipidemia, and anti-tumor properties. Integrating phylogenetics and network pharmacology enabled exploring the intricate links between metabolite profiles, traditional efficacy, and modern pharmacology of Dracocephalum and its related genera. This study illustrates how to discover potential medicinal value from closely related ethnomedicinal taxonomic groups.Another endeavor in Vol III is reconstructing the phylogenetic tree of Glycyrrhiza and related subfamilies of Fabaceae based on the whole chloroplast (cp) genome sequences (Wu et al., 2024).China has eight species of Glycyrrhiza (Chen et al., 2020), which can be classified into two sections based on the presence of glycyrrhizic acid: section Glycyrrhiza (G. uralensis Fisch., G. glabra Linn., G. inflata Batal., G. aspera Pall., G. eglandulosa X. Y. Li) and section Pseudoglycyrrhiza (G. pallidiflora Maxim., G. squamulosa Franch., G. yunnanensis Cheng f. et L. K. Dai ex P. C. Li). The cp genome-based phylogeny confirmed this classification, and suggested that G. gobica Grankina and G. uralensis clustered together, G. laxissima Vassilcz. and G. aspera clustered together, and other taxa, which are treated as synonyms of G. uralensis, G. glabra or G. aspera in Flora of China, should be considered as independent species. The North American species G. lepidota had a lower content of glycyrrhizic acid and was in another group, indicating that the groups containing glycyrrhizic acid were not monophyletic, i.e. the incongruence between phylogenomics and chemotaxonomy. The cp genome-based phylogeny also revealed distinct intraspecific divergence in 38 Artemisia annua strains (Ding et al., 2024). These results are very beneficial for us to fully understand the complexity of medicinal kinship at various taxonomic levels.It is expected that the metabolomic analyses and phytometabolite content determination could reveal the overall similarity of phytometabolite profiles between medicinally important species, such as Astragalus membranaceus (Li et al., 2024), Dioscorea opposita, and Rehmannia glutinosa, and phylogenetically related species, and both molecular authentication and chemotaxonomy could be used to discriminate them from common adulterants. On the other hand, the R&D of innovative herbal medicine formulas can also benefit from detailed pharmacophylogenetic studies, as closely related species can be added to the medicine formulas, and various combinations of them can be tried to observe changes in therapeutic effects, which may improve the efficacy of existing herbal formulas or expand novel therapeutic approaches. The cp genome is an useful genetic resource for phylogeny and evolution studies at both species and subspecies/population levels, while the interspecific/intraspecific chemodiversity could lead to development of novel clinical utility.In summary, the greatest truths are the simplest; taxa in sister phylogenetic groups have relatively similar requirements for ecological environment conditions (Hao et al., 2024b), they have closely related genetic features, and are more likely to evolve analogous biosynthetic pathways, therefore their chemical ammunition depot could be more similar, resulting in the global resemblance of bioactivity or therapeutic efficacy (Hao et al., 2024a). However, if we want to condense scientific hypotheses and practical solutions from the complex phenomena and vast amounts of data, hard work is essential. Integrating ecological and evolutionary factors helps to gain a more inclusive understanding of phytochemical changes in changing environments (Hao et al., 2023b). With any luck the papers in Volumes I-III of Research Topic could serve as valuable references and enhance researchers' cognizance of pharmacophylogeny, and we wish more scholars intentionally leverage pharmacophylomic methods to the conservation, exploration, and utilization of medicinal species.