1 Introduction

Angelica sinensis, Danggui in Chinese, is one of the most famous medicinal plants in traditional Chinese medicine. It has been used extensively for thousands of years to “nourish blood”, “promote circulation”, and “regulate menstruation”. Its dried root is used in classical prescriptions treating blood deficiency, pain, inflammation, and gynecological disorders. Modern pharmacology has revealed that A. sinensis possesses a wide range of bioactivities, including antioxidant, anti-inflammatory, neuroprotective, cardioprotective, and immunomodulatory. It is evident that the diverse secondary metabolites, mainly phenylpropanoids, lie at the heart of this varied array of therapeutic properties. Amid the increasing demand worldwide for natural medicine and functional plant resources, elucidation of the biochemical basis of A. sinensis quality formation has been revised up as a central research priority in the science of medicinal plants (Zhi et al., 2024).

The most abundant and pharmacologically important classes of secondary metabolites in A. sinensis are the phenylpropanoids, which include key subclasses represented by ferulic acid and its derivatives, coumarins, including osthole, scopoletin, and umbelliferone, and lignans. Structurally derived from L-phenylalanine, they play key roles in the defense of plants, in the maintenance of redox homeostasis, and in stress responses. The phenylpropanoids of A. sinensis represent major active constituents that take part in antioxidant action, anti-inflammatory activity, vasodilatory action, modulation of blood rheology, and the protection of neuronal cells. Ferulic acid is considered as a quality marker in modern pharmacopeias. Biosynthesis and regulation of these phenylpropanoids are important to understand the molecular basis of medicinal functions of the plant (Ren et al., 2025).

Over the past two decades, great advances have been achieved in the identification of phenylpropanoid compounds and their corresponding biosynthetic genes. However, several scientific challenges are yet to be surmounted: first, the metabolic network is highly complex, with many parallel and branched pathways and enzyme families with redundant or specialized functions; second, the spatial and temporal distribution of metabolites within tissues, during development, and under different environmental conditions has remained incompletely characterized; and third, although transcriptome and metabolome studies have identified key metabolic signatures, the functional validation of enzymes, transcription factors, and regulatory modules remains unfinished. Besides, the differences caused by cultivation region, processing method, and germplasm variation further complicate the association between phenotype and genotype and quality chemicals. Advanced multi-omics integration, gene-function verification systems, and synthetic biology approaches are called for to respond to this requirement (Xu et al., 2019; Chen et al., 2024).

This study offers a comprehensive overview of recent advances made in research into phenylpropanoid biosynthesis in A. sinensis. It identifies major categories of phenylpropanoids according to their chemical features, distribution patterns, and pharmacological relevance. Current knowledge on core biosynthetic pathways is then summarized, including the catalytic function of key enzymes and the biochemical processes underpinning structural diversification. This study hopes to provide an integrated foundation for future research and practical innovation in the metabolic study and utilization of phenylpropanoids in A. sinensis.

2 Types and Chemical Characteristics of Phenylpropanoid Compounds in Angelica sinensis

2.1 Major categories of compounds

It is rich in various phenylpropanoid-derived secondary metabolites. There are three major classes of compounds: phthalides, coumarins, and lignans. The phthalides, mainly ligustilide, butylidenephthalide, and ferulic acid derivatives, are the most prevalent and pharmacologically important constituents, often playing roles as quality markers of the herb (Xu et al., 2019; Sun et al., 2024; Zou et al., 2024). The coumarins, such as osthole and umbelliferone, are major compounds contributing to the medicinal properties, showing a great variety of structures (Han et al., 2022; Li et al., 2023). Lignans are relatively less present but similarly contribute to the chemical complexity and bioactivity of A. sinensis.

2.2 Structural features and structure-function relationships

Phthalides in A. sinensis range from simple monomers to complex dimers and polymers, covering various ring size variations, substituents, and stereochemistries. These structural diversities greatly affect their bioactivities; for example, dimeric phthalides often exhibit strong anti-inflammatory activities compared with monomers. Wen et al. (2025), Zhang et al. (2025), and Zou et al. (2024) reported that the position and configuration of chiral centers in phthalide molecules may cause significant changes in the bioactivity and pharmacokinetics of phthalides. Coumarins contain a benzopyrone skeleton, and their functionalization-one or more furan or pyran rings-affects antioxidant, neuroprotective, and anti-inflammatory activities. Han et al. (2022) and Li et al. (2023) reported that lignans, which contain characteristic dimeric phenylpropanoid skeletons, exert additional antioxidant and estrogenic activities.

2.3 Variations in compound contents among plant organs, geographical origins, and processing methods

The content and distribution of phenylpropanoids vary significantly among different organs of the plant, their geographical origins, and the method adopted for their processing. For instance, ferulic acid and ligustilide were distributed unevenly in the head, body, and tail of the root, with mostly higher contents of ferulic acid in the tail (Xu et al., 2019; Qin et al., 2024). Geographical origin controls the accumulation of key compounds, since this factor depends on environmental factors such as nutrient content in the soil and climatic conditions that determine metabolic profile (Jing et al., 2024; Sun et al., 2024; Yu et al., 2025). Xu et al. (2020) Stir-frying and vinegar treatments are capable of further modifying its chemical composition, increasing the contents of some phenolic acids and coumarins, which are associated with enhanced antioxidant activities. These variations affect the quality control and therapeutic consistency of the medicine (Chen et al., 2023).

2.4 Overview of pharmacological activities of phenylpropanoids

Among the phenylpropanoid compounds of A. sinensis, a wide range of pharmaceutical activities has been demonstrated. The majority of them are highly effective antioxidants and anti-inflammatory agents, while phthalides and coumarins were highly inhibitive against nitric oxide production and pro-inflammatory cytokines' release (Wen et al., 2025; Zhang et al., 2025). They further improve blood circulation and inhibit platelet aggregation, producing neuroprotective effects, and hence justify traditional applications in cardiovascular and neurological conditions (Xu et al., 2019; Li et al., 2023; Zou et al., 2024). Furthermore, certain phenylpropanoids possess anti-osteoporotic, antifibrotic, and immunomodulatory activities that extend the therapeutic perspectives for A. sinensis (Chen et al., 2024) (Figure 1).

Figure 1 Pharmacological activity of benzo-phenyl compounds from angelica sinensis (Adopted from Chen et al., 2024)

3 Biosynthetic Pathways of Phenylpropanoid Compounds in Angelica sinensis

3.1 Overview of the phenylpropanoid pathway mediated by phenylalanine ammonia-lyase (PAL)

The phenylpropanoid pathway of Angelica sinensis is initiated by PAL, which catalyzes the deamination of L-phenylalanine to cinnamic acid. This is an important entry point in the biosynthesis of a great array of diverse secondary metabolites, including coumarins, flavonoids, and lignins. PAL has been considered the rate-limiting enzyme, and it is highly expressed in the root tails, which is coincident with the ferulic acid content and other phenylpropanoid derivatives (Xu et al., 2019; Yang et al., 2020). It proceeds down the pathway through a series of enzymatic steps: hydroxylation and activation to CoA esters, forming precursors for downstream products, as described by Roy et al. (2016).

3.2 Roles and regulation of key enzymes

Key enzymes of the pathway include PAL, cinnamate 4-hydroxylase (C4H), 4-coumarate-CoA ligase (4CL), coumarate 3-hydroxylase (C3H), caffeic acid O-methyltransferase (COMT), and caffeoyl-CoA O-methyltransferase (CCoAOMT). These enzymes are expressed differentially in root parts: the highest expression levels for transcripts PAL, C3H, and CQT in the tails reflect higher biosynthetic activity for ferulic acid and its derivatives (Xu et al., 2019; Yang et al., 2020). The control is at the level of transcription and epigenetic modifications, whereby DNA methylation, most of which is CHH-type, affects the expression of key genes such as AsCOMT1, implicated in the biosynthesis of both lignin and ferulic acid (Li et al., 2023).

3.3 Enzymes involved in coumarin backbone formation

Coumarin biosynthesis relies on p-coumaroyl-CoA 2'-hydroxylase (C2'H) for the synthesis of umbelliferone; UbiA PTs for prenylation; and cytochrome P450 cyclases, belonging to the CYP736 subfamily for formation of the core skeleton. These β-glucosidases participate in the conversion process of glycosylated coumarins to their aglycone forms, as in converting scopolin into scopoletin in other related Angelica species (Han et al. 2022; Wang et al., 2024; 2025) (Figure 2). CoA-dependent processes are required for hydroxycinnamic acid activation in order to enable further modifications and the assembly of the coumarin backbone (Roy et al., 2016; Xu et al., 2019).

Figure 2 Cumarin biosynthesis in Angelica sinensis (Adopted from Han et al., 2022)

3.4 Downstream modifications and structural diversification

Through hydroxylation by CYPs, methylation by COMT/CCoAOMT, glycosylation mediated by UDP-glycosyltransferases, and acylation, the structural diversification of phenylpropanoids is achieved. More specifically, glycosylation controls solubility, stability, and biological activity and hence is one of the major regulatory points for phenylpropanoid homeostasis (Roy et al., 2016). Various such modifications contribute to coumarin, flavonoid, and lignin diversity in A. sinensis (Xu et al., 2019; Li et al., 2023).

3.5 Interactions and metabolic flux partitioning between polyphenols and coumarins

Metabolic flux of the phenylpropanoid pathway is branched in different directions, partitioned between polyphenols, including flavonoids and lignins, and coumarins. Partitioning of metabolic flux is influenced by pathway gene expression and regulatory factors, in addition to environmental and developmental cues. As such, higher expression of PAL, C3H, and CQT in root tails favors ferulic acid and coumarin biosynthesis, whereas methylation status can shift flux toward either lignin or coumarin production (Xu et al., 2019; Li et al., 2023). Gene family expansions and transcriptional regulation are at the heart of this metabolic flexibility, as highlighted by multi-omics analyses (Han et al., 2022).

4 Genes and Regulatory Networks in Phenylpropanoid Biosynthesis of Angelica sinensis

4.1 Identified key genes

The key genes in the phenylpropanoid biosynthesis pathway of A. sinensis are PAL, 4CL, HCT, and several members of the CYP450 family. Multi-omics and transcriptomic studies on these enzymes also revealed that most of them have multiple isoforms and gene copies, among which PAL, C3H, and CQT exhibit high expression in root tails to promote the biosynthesis of ferulic acid and coumarin (Xu et al., 2019; Yang et al., 2020). The expansion of other gene families, such as PTs and CYPs, also supported the metabolic diversity in A. sinensis (Han et al., 2022; Li et al., 2023).

4.2 Transcription factors

These include MYB, bHLH, WRKY, and AP2/ERF transcription factor families, which have been identified as playing basic roles in the transcriptional activation of genes in the phenylpropanoid pathway. The R2R3-MYB TFs are considered master regulators that regulate the transcription of structural genes responsible for flavonoid, anthocyanin, and lignin biosynthesis (Du et al., 2022). MYB3 was identified to be a key regulator of flavonoid and anthocyanin synthesis in coexpression network analyses with positive correlation to key biosynthetic enzymes in A. sinensis (Wu et al., 2024). Other TFs involved in the coordinated regulation of phenylpropanoid metabolism include bHLH and WRKY as identified by Du et al. (2022).

4.3 Epigenetic regulation

Epigenetic mechanisms, especially DNA methylation, are important to phenylpropanoid biosynthesis in A. sinensis. Genome-wide methylation studies reveal that CHH-type methylation in promoter regions is related to the regulation of such key genes as AsCOMT1 participating in ferulic acid and lignin synthesis. Higher DNA methylation degree corresponds with high gene expression and secondary metabolite accumulation-a fact emphasizing its regulatory significance (Yuan et al., 2024). Histone modifications, though less characterized in A. sinensis, are also involved in the regulation of genes of phenylpropanoid metabolism in other plants.

4.4 Regulatory networks: Metabolic pathways and TF-structural gene coordination

In A. sinensis, the complex interactions between metabolic pathways and structural gene coordination by TFs take place within regulatory networks (Xu et al., 2019; Wu et al., 2024). Weighted gene co-expression network analysis has identified modules of co-expressed genes with TFs that control the spatial and temporal expression of the genes responsible for phenylpropanoid biosynthesis. Such networks ensure that bioactive compound biosynthesis is coordinated-with TFs such as MYB, bHLH, and WRKY integrating developmental and environmental signals to modulate pathway flux (Du et al., 2022).

4.5 Gene family expansion and A. sinensis-specific evolutionary adaptations

A. sinensis has considerable expansions of the phenylpropanoid biosynthesis gene families, including but not limited to PTs, CYPs, and other pathway enzymes. These are evident through whole-genome duplication and tandem duplication events, which have enabled metabolic diversification and adaptation. By comparative genomics, such expansions into CYPs would seem unique to A. sinensis and its close Apiaceae relatives, thereby underpinning the evolution of unique coumarin and polyphenol profiles (Han et al., 2022; Li et al., 2023). Such adaptations underpin the medicinal properties and ecological success of this plant.

5 Multi-omics Insights into the Regulation of Phenylpropanoid Biosynthesis in A. sinensis

5.1 Transcriptomic analysis of pathway gene expression patterns

Transcriptomic studies have shown that the main phenylpropanoid biosynthesis genes display tissue- and stage-specific expressions, such as PAL, C3H, CQT, COMT, and 4CL. For instance, high expressions of PAL, C3H, and CQT transcripts in the root tail are coincident with higher ferulic acid contents, and thousands of unigenes exhibit specific expression patterns in heads, bodies, and tails (Xu et al., 2019; Yang et al., 2020). The differential expression of genes also explains the flavonoid and anthocyanin accumulation in cultivar specificity.

5.2 Proteomic and phosphoproteomic insights into enzyme activity regulation

Though few direct proteomic and phosphoproteomic studies have been conducted in A. sinensis, multi-omics integrations have pinpointed candidate enzymes and isoforms that participate in the biosynthesis of phenylpropanoids and phthalides. Enzyme activities are usually inferred from transcript abundance and metabolite accumulation. Validation through heterologous expressions and enzyme assays has been performed for a number of key steps (Feng et al., 2022; Li et al., 2023). These approaches contribute to the linking of gene expression with functional enzyme activity and metabolite profiles.

5.3 Metabolomic correlations across developmental stages and plant tissues

Metabolomic profiling reveals that the phenylpropanoid compounds, including ferulic acid and flavonoids, are distributed variably among root parts and cultivars. The highest levels of ferulic and caffeic acid have been detected in the root tail, coinciding with the expression of biosynthetic genes (Yang et al., 2020). Metabolomic variation also reflects developmental and environmental influences, such as light exposure, influencing the accumulation of metabolites and gene expression alike (Su et al., 2024).

5.4 Applications of single-cell and spatial omics in tissue-specific biosynthesis

Single-cell and spatial omics approaches are so far barely applied to A. sinensis, but the few current transcriptomic and metabolomic analyses at tissue levels-giving priority to heads, bodies, and tails-offer spatial resolution of the biosynthetic activity. Such studies have identified that some tissues are specialized in the production of some phenylpropanoids, hence the value of single-cell and spatial omics for finer mapping in the future (Xu et al., 2019).

5.5 Multi-omics integration for pathway modeling and prediction of new metabolic nodes

It enables the identification of expanded gene families, regulatory modules, and candidate metabolic genes through the integration of genomic, transcriptomic, and metabolomic data. This kind of systems approach has revealed novel biosynthetic nodes, including expanded prenyltransferases and O-methyltransferases, and allows pathway modeling for metabolic engineering and synthetic biology applications (Li et al., 2023). Multi-omics integration would be necessary for the prediction of regulatory interactions that may guide the discovery of new bioactive compounds.

6 Metabolic Engineering and Synthetic Biology in Phenylpropanoid Production

6.1 Gene overexpression, RNA interference, and CRISPR/Cas9 technologies

Gene overexpression and RNA interference (RNAi) remain foundational for the modulation of phenylpropanoid pathways. The recent development of CRISPR/Cas9 and CRISPR/dCas9 has, therefore, given rise to highly specific genome editing and transcriptional regulation, such as DNA-free editing and multiplexed gene control. Application to key pathway genes including 4CL has thus far demonstrated successful targeted mutagenesis and pathway modification in both plants and microbes (Badhan et al., 2021; Karlson et al., 2021; Rai et al., 2025).

6.2 Heterologous expression systems for biofactory construction

Yeast and microbial platforms are two of the most common hosts used for heterologous expression of phenylpropanoid biosynthetic genes. Recently, modular approaches to synthetic biology have allowed the rapid assembly of multigene pathways that produce compounds such as coumaric acid and naringenin from simple feedstocks. These systems can be scaled up and optimized for industrial production (Ramzi et al., 2018; Mejía-Manzano et al., 2023; Akinola et al., 2024).

6.3 Pathway optimization strategies

Optimization strategies include enzyme engineering, metabolic flux regulation, and forming multi-enzyme complexes. CRISPRi and similar techniques can achieve multiplexed repression of genes, increasing product titers through fine-tuning metabolic pathways. Engineering side reactions and balancing redox reactions further improved yields in the strains engineered by Lehka et al. (2016) and Harvey et al. (2018).

6.4 Synthetic biology-driven high-yield strain development

These high-yielding engineered strains were developed using systems biology, combinatorial pathway design, and advanced vector methods. These approaches make possible the integration of multiple pathway genes and their proper expression balance for the efficient biosynthesis of target phenylpropanoids (Mejía-Manzano et al., 2023; Akinola et al., 2024).

6.5 Industrial production potential and bottlenecks

While most of the processes are now within an industrially feasible production scale, several issues caused by enzyme promiscuity and toxicity of intermediates are still present; regulatory problems with GMOs also arise. Further engineering of the strain and process optimization are required for innovations beyond such bottlenecks to reach their commercial viability (Akinola et al., 2024).

7 Application Prospects of Phenylpropanoid Compounds from Angelica sinensis

7.1 Enhancement of medicinal value and identification of quality markers

The main active pharmaceutical ingredients contributing to the medicinal efficacy of A. sinensis are phenylpropanoids, such as ferulic acid. An integrated approach of chemical and transcriptomic investigations identified that the distribution of phenylpropanoids differs in various parts of the roots, with higher contents of ferulic acid in the tail and increased expression of its biosynthetic genes, PAL, C3H, and CQT. This is also the basis for the difference in clinical efficacy and justifies the use of ferulic acid and related compounds as quality markers for standardizing medicinal products (Xu et al., 2019; Yang et al., 2020). Advanced analysis methods can be applied for a comprehensive quality evaluation of different origins and processing methods, which further ensure product consistency (Feng et al., 2022; Sun et al., 2024).

7.2 Mechanistic studies supporting new drug discovery

Some active principles, such as phenylpropanoid and phthalide compounds, have also been identified from the mechanistic studies with significant anti-inflammatory, antioxidant, and anti-osteoporotic activities. For instance, some phthalide dimers and monomers from A. sinensis showed potent anti-inflammatory and anti-osteoporotic activities; some act on Nur77 and NF-κB pathways of defined molecular targets (Xia et al., 2024; Zou et al., 2024; Wen et al., 2025). These will provide a basis upon which new drugs can be developed using the A. sinensis phennylpropanoids.

7.3 Molecular breeding and development of high-quality A. sinensis cultivars

The major genes and regulatory networks in phenylpropanoid biosynthesis involved have been identified through genomic and multi-omic studies, therefore allowing marker-assisted selection and molecular breeding of improved cultivars. For example, genetic and epigenetic modifications related to the development of high ferulic acid and flavonoid content or those resistant to early bolting-a key factor in affecting root quality-can be used. Such progress, described by Li et al. (2023), Han et al. (2022), and Han et al. (2023), enables the breeding of high-yielding, high-quality A. sinensis for both medicinal and industrial applications.

7.4 Potential for functional foods and natural product industrialization

Accordingly, phenylpropanoids and related polysaccharides from A. sinensis possess huge potential as functional food ingredients based on the bioactivity and safety profiles displayed. Antioxidant, immunomodulatory, and anti-inflammatory properties warrant their inclusion in health foods and nutraceuticals (Hou et al., 2021). An improved quality control system and strategy of large-scale cultivation with ecological and microecological regulation will promote industrialization and further application in food and health areas (Jing et al., 2024; Sun et al., 2024).

8 Concluding Remarks

The research on the biosynthetic pathways of phenylpropanoids in Angelica sinensis has achieved noticeable improvement in recent years, facilitated by genomics, transcriptomics, metabolomics, and biochemical characterization. Functional annotation has identified important enzymes such as PAL, C4H, 4CL, COMT, and CCoAOMT, while many downstream modifications that give rise to the structural diversification of coumarins, ferulic acid derivatives, and lignans have been elucidated. Considerable efforts have also gone into mapping developmental and tissue-specific accumulation patterns and the identification of associated transcription factors underlying pathway regulation.

Coupled with these advances, several gaps still remain. Most of the candidate enzymes predicted from omics datasets are yet to be experimentally verified for their functions. Spatial organization of biosynthetic pathways, including enzyme complexes and transport processes, has not been well elucidated. Similarly, interplay among metabolic flux, environmental cues, and hormonal regulation remains incompletely resolved. Further, incomplete genome assemblies and scarce genetic resources in A. sinensis continue to impede the precision of functional characterization.

For a deeper understanding of the biosynthetic architecture, pathway-associated genes have to be systematically identified and verified, including those encoding minor or yet-undiscovered enzymes involved in tailoring reactions such as glycosylation, methoxylation, and acylation. Further investigation of regulatory networks involving MYB, bHLH, AP2/ERF, and WRKY transcription factors, in particular combinatorial regulation and interactions with chromatin-level modifications, is needed. Integration of gene function studies with promoter analysis, epigenetic profiling, and single-cell or spatial transcriptomics will be required to elucidate cell-specific and developmental regulation mechanisms. Such studies would provide insight into allocation of flux among the distinct phenylpropanoid branches and the creation of characteristic metabolite profiles of A. sinensis.

Furthermore, such understanding on phenylpropanoid biosynthesis provides a scientific basis for the innovative use of A. sinensis germplasm and allows for target breeding to improve quality, metabolite profiles, and stress tolerance of this species. Knowledge related to the regulation of biosynthesis will contribute to the development of molecular markers and elite cultivars, as well as standardized cultivation strategies. Moreover, metabolic engineering and synthetic biology enable the sustainable production and at-scale production of high-value bioactives to meet the demands for the creation of new pharmaceuticals and functional foods and health products. In addition, the establishment of integrated biotechnological platforms and enlarged high-throughput screening pipelines will further facilitate the industrialization of phenylpropanoid derivatives and enhance the competitiveness of A. sinensis-based natural products.

Acknowledgments

The authors extend sincere gratitude to the research team for their meticulous assistance and unwavering support throughout the study's execution and data collection process. We also express heartfelt appreciation to the two anonymous reviewers for their valuable feedback and constructive suggestions during the peer review process, which have significantly contributed to refining the paper's quality and enhancing its academic rigor.

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.

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