Medicinal plants play pivotal roles in human development and have been used from the prehistoric times to present day. According to the World Health Organization, 80% of the human population in developing countries relies on traditional medicines, mostly plant-based drugs, for primary healthcare needs. At present, at least 25% of the drugs worldwide are directly or indirectly derived from medicinal plants, which remain the main source of drugs. For example, artemisinin, derived from Artemisia annua, is widely used for treating malaria (Ansari et al., 2013). Ajuga bracteosa is a high-value medicinal plant that has been recommended as a treatment for gout rheumatism, paralysis, and amenorrhea (Rukh et al., 2019). Secondary metabolites (SMs) serve as the material basis of the clinically curative effects of medicinal plants. SMs refer to small molecular organic compounds not directly involved in plant growth and development, but are essential for the long-term survival of plants (Fraenkel, 1959; Demain and Fang, 2000). Besides their medicinal uses, SMs are also widely used in cosmetics and healthcare products (Craker and Gardner, 2006; Mathur and Velpandian, 2009; Schmidt, 2012).

Biosynthesis and accumulation of SMs in medicinal plants are affected by environmental factors, such as water, light, temperature, soil properties, and chemical stress (Verma and Shukla, 2015; Li et al., 2020). Among these factors, light is reported to affect the accumulation of almost all types of SMs. Light quality, light intensity, and photoperiod affect the SM content of plants. For example, the composition and content of SMs in the same plant species vary greatly among different regions because of the variation in light conditions (Huang and Liu, 2015). Controlled growing systems using artificial lighting have been widely applied with the increasing demand for natural products. These systems are initially developed for the production of out of season crops and vegetables. In recently years, they are also used to enhance the SMs yields in medicinal plants (Askari-Khorasgani and Pessarakli, 2019; Moon et al., 2020; Malik et al., 2021). Artificial lights take important place in controlled growing systems and light emitting diodes (LEDs) are supposed to be optimal artificial light sources at present time (Jung et al., 2021). Compared with other types of lamps, such as fluorescent, high-pressure sodium (HPS), and metal-halide, LEDs show equivalent or higher luminous efficacy, lack of radiant heat, and longer lifespan (Loi et al., 2021). Besides, LED can also produce the monochromatic light wavelength and make it more convenient to change the light quality constitution in the controlled growing systems (Palmitessa et al., 2021). Understanding how light affects SM biosynthesis is essential for the cultivation of medicinal plants in a controlled environment as well as under open field conditions. In this review, we discuss the roles of light in the accumulation of different types of SMs, with the aim to identify the gaps in research and to provide a reference for the further investigation of the mechanism underlying light-mediated SM biosynthesis in medicinal plants.

Based on their structures and biosynthetic pathways, plant SMs are mainly divided into polyphenols (phenolics), terpenoids, and alkaloids (Chiocchio et al., 2021). Polyphenols are a large and complex family of phytochemicals containing at least one aromatic ring and a hydroxyl group as functional derivatives. Over 8,000 polyphenols have been identified in plants to date. They are present in almost all plant species and have gained considerable attention because of their nutritional and pharmaceutical applications (Balasundram et al., 2006). According to the biosynthetic pathways, basic skeletons, and hydroxyl groups, polyphenols are categorized into different sub-classes, including coumarins, lignans, phenolic acids, flavonoids, and tannins (Huang and Liu, 2015; Chiocchio et al., 2021). Coumarins (C₆-C₃) are a class of lactones structurally constructed by a benzene ring fused to α-pyrone ring, such as aesculin, cnidium lactone, and alpha-Angelica lactone. Lignans [(C₆-C₃)₂] are phenolic dimers with a 2,3-dibenzylbutane skeleton, such as phyllanthin, arctiin, and podophyllotoxin. Phenolic acids present compounds containing a carboxylic group among the substituents on the benzene ring, including benzoic acid derivates (C₆-C₁) and hydroxycinnamic derivates (C₆-C₃). Flavonoids (C₆-C₃-C₆) refer to compounds consisting of two benzene rings linked by a short three carbon chain, such as chalcones, flavones, flavonols, dihydroflavones, dihydroflavonols, isoflavones, and dihydroisoflavones. Tannins are high molecular polyphenols polymerized by flavonoids units (condensed tannins) or gallic acid esterified with monosaccharide (hydrolysable tannins; King and Young, 1999). Figure 1A shows structures of some common bioactive polyphenols in medicinal plants, including three phenolic acids (salvianolic acid B, chlorogenic acid, and rosmarinic acid), two phenylethanol glycosides (verbascoside and salidroside), and one flavanone derivate (rutin). Polyphenols are biosynthesized via phenylpropanoid pathway in plants, they share a common upstream biosynthetic pathway derived from the shikimic acid pathway, but the downstream biosynthetic pathways of different polyphenols are distinct (Figure 1B; Dixon and Paiva, 1995).

Terpenoids are compounds with isoprene as the structural unit. According to the number of isoprene structural units, terpenoids are divided into five categories: monoterpenes, sesquiterpenes, diterpenes, triterpenes, and tetraterpenes (Bohlmann et al., 1998). Figure 2A shows structures of some common bioactive terpenoids in medicinal plants, including one sesquiterpene (artemisinin), three diterpenes (cryptotanshinone, tanshinone II_A, and paclitaxel), and two triterpenes (cucurbitacin I and oleanolic acid). Terpenoids are synthesized via two parallel upstream pathways: the mevalonate pathway (MVA) and methylerythritol-4-phosphate pathway (MEP; da Silva et al., 2017). Acetyl-CoA acts as the precursor of terpenoids in the MVA pathway, whereas pyruvate and glyceraldehyde-3-phosphate (G3P) serve as precursors in the MEP pathway. These precursors are converted to isopentenyl pyrophosphate (IPP) through a series of enzymatic reactions, which is then converted to its isomer dimethyl-allyl pyrophosphate (DMAPP) by isopentenyl diphosphate isomerase (IDI). Both DMAPP and IPP are converted to geranylgeranyl diphosphate (GGPP) by geranylgeranyl diphosphate synthase (GGPPS), and then, GGPP is used to produce diterpenes, tetraterpenes, and their derivatives (Newman and Chappell, 1999). DMAPP and IPP are also converted to farnesyl diphosphate (FPP) and geranyl diphosphate (GPP) by farnesyl diphosphate synthase (FPPS) and geranyl diphosphate synthase (GPPS), respectively. Both FPP and GPP then act as precursors of monoterpenes, sesquiterpenes, and triterpenes (Figure 2B; Chappell, 1995; Bergman et al., 2019).

Alkaloids form a large class of heterocyclic nitrogen organic compounds, with over 10,000 isolated to date. Given their antitumor, antibacterial, and anti-inflammatory activities, alkaloids have been widely used for the production of medications (Jain et al., 2019; Zhang et al., 2021). Depending on their biosynthetic pathways and chemical structures, alkaloids are classified into five groups: terpene indole, benzylisoquinoline, tropine, purine, and pyrrolizidine alkaloids (Bhambhani et al., 2021). Figure 3A shows structures of some common bioactive alkaloids in medicinal plants, including three monoterpenoid indole alkaloids (MIAs; vindoline, vinblastine, and camptothecin), one benzylisoquinoline alkaloid (berberine), and two tropine alkaloids (hyoscyamine and scopolamine). The accumulations of MIAs and tropane alkaloids have been reported to be affected by light. Biosynthetic pathways of MIAs and tropane alkaloids have been characterized. MIAs are synthesized via two parallel upstream pathways, generating tryptamine and secologanin, which are converted to strictosidine by strictosidine synthase (STR), and then to various MIAs, such as camptothecin, serpentine, and vinblastine (Herrmann, 1995; Radwanski et al., 1996; Huang et al., 2016). Ornithine and phenylalanine, the initial precursors of tropine alkaloids, are converted to littorine, which is then converted to anisodamine and scopolamine via several enzymatic reactions (Figures 3B,C; Nguyen et al., 2015; Qiu et al., 2020).

Optimal light conditions required for growth and development differ among different medicinal plant species. According to their sunlight intensity requirements, medicinal plants are classified into three types: heliophytes, sciophytes, and intermediates. Similar to other physiological processes, the accumulation of SMs in medicinal plants is significantly affected by light intensity (Chen et al., 2017; Li et al., 2020). Generally, high light intensity promotes SM production in heliophytes, such as Ginkgo biloba (Xu et al., 2014), Lonicera japonica (Fang et al., 2020), Tabernaemontana pachysiphon (Hoft et al., 1996), and Andrographis paniculata (Saravanan et al., 2008), while low light intensity promotes SM production in sciophytes, such as Glechoma longituba (Zhang et al., 2015), Changium smyrnioides (Wang et al., 2017), Polygonum minus (Mohd Yusof et al., 2021), and Panax ginseng (Jung et al., 2020). Concentration and yield are two important parameters that should be considered for SM production in medicinal plants. For example, Li et al. (2018a) reported that 30 and 50% sunlight are better light conditions than 10 and 100% sunlight, for total alkaloid production in Mahonia breviracema, as the former light intensities result in higher biomass. Similarly, in G. longituba, the concentration and yield of ursolic acid and oleanolic acid were stimulated under 33% sunlight and 16% sunlight, respectively, compared with other light intensities (Zhang et al., 2015).

Light intensity also affects the chemical composition of medicinal plants. For instance, Xu et al. (2020) fond that moderate shade (38.8% of the control) promoted the accumulation of C₆C₁- and C₆C₃-type phenolics, while severe shading (16.9% of the control) stimulated the accumulation of C₆C₃C₆-type phenolics in Eleutherococcus senticosus. Santos Lazzarini et al. (2018) treated Lippia gracilis with different light intensities and showed that the chemical composition of seedlings in the 26 μmol m⁻² s⁻¹ group was more complex, with more monoterpene hydrocarbons and less aromatic monoterpenes, than those in other treated groups. In M. breviracema, light intensity had different effects on the production of alkaloids and essential oils; alkaloid content was significantly enhanced in the 30 and 50% sunlight groups, while the accumulation of essential oils increased linearly with the increase in light intensity, reaching maximum levels in the full (100%) sunlight group (Li et al., 2018a).

Photoperiod is one of the critical environmental factors that regulate the growth and development of medicinal plants and is often closely related to other environmental factors, such as latitude, slope direction, and seasonal changes (Liebelt et al., 2019). Depending on the day length or amount of light required for flowering, medicinal plants are classified into long-day, short-day, and intermediate-day plants (Huang and Liu, 2015). Different plant species adapt to changes in the photoperiod through various physiological modifications, one of which is by altering the accumulation of SMs (Moyo et al., 2014; Zahir et al., 2014; Liebelt et al., 2019).

In many medicinal plants, photoperiod promotes the accumulation of SMs. For example, Fazal et al. (2016b) optimized the conditions required for P. vulgaris suspension culture and found that the biomass and SM content were higher under 18-h light/12-h dark (18L/12D), 16L/14D, and 14L/16D photoperiods compared with the control (16L/8D). Kumar et al. (2020) found that Basella rubra callus cultures under the 16:8 h photoperiod produced the highest amount of phenolics compared with those under continuous light and continuous dark conditions. Wu et al. (2007) studied the effects of photoperiod on the growth and caffeic acid derivative content of the adventitious root cultures of Echinacea purpurea, and found that the accumulation of caffeic acid derivatives was optimum in cultures grown under 3-h light/21-h dark conditions. There are also many studies which report that continuous light or continuous dark is more efficiency to stimulate the bioactive compounds biosynthesis compared with photoperiod in some medicinal plants. For instance, de Castro et al. (2019) found that 24-h d⁻¹ light was the best light condition for enhancing the growth and essential oil content of Lippia alba seedlings grown in vitro. Anjum et al. (2017) treated the cell cultures of Linum usitatissimum with different photoperiods, and showed that continuous dark conditions led to the greatest increase in total phenolics (116.85 mg L⁻¹) and total flavonoids (37.05 mg L⁻¹). Photoperiod also affects the chemical composition of medicinal plants. Tusevski et al. (2013) found that hairy roots of Hypericum perforatum cultured under 16-h light/8-h dark photoperiod showed de novo biosynthesis of two phenolic acids, three flavonol glycosides, and five xanthones compared those cultured under continuous dark. Fonseca et al. (2006) revealed that dark incubation decreased the content of parthenolide and increased the content of total phenolics in Tanacetum parthenium, while photoperiod showed an opposite effect on the accumulation of these compounds.

In this review, we summarized the regulatory roles of light quality, light intensity, and photoperiod in SM accumulation in medicinal plants and the known mechanisms underlying these roles (Figure 4). Generally, when plants are exposed to UV-B radiation, the UVR8 homodimer undergoes monomerization and interacts with CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1), which increases COP1 stability and induces LONG HYPOCOTYL 5 (HY5) expression. HY5 is a core transcription factor in the light signaling pathway that regulates expression of genes encoding transcription factors or key enzymes involved in the biosynthesis of SMs, to affect the accumulation of SMs under UV-B (Gangappa and Botto, 2016; Liu et al., 2018b; Yang et al., 2018). Phytochromes (phyA and phyB) and cryptochromes (cry1 and cry2) regulate the accumulation of SMs in a different way (Hemm et al., 2004; Chen et al., 2006; Li et al., 2014; Fu et al., 2021a). These photoreceptors interact with COP1 or SUPPRESSOR OF PHYA-105 (SPA) in a light-dependent manner and inhibit the E3 ubiquitin ligase activity of the COP1–SPA complex. Under dark conditions, COP1 enters the nucleus and mediates the degradation of the HY5 protein through the 26S proteasome. Under blue, red, and far-red light conditions, HY5 functions its roles normally and promotes the production of SMs. In A. annua, HY5 binds to the promoters of some transcription factor genes, such as AaWRKY9, GLANDULAR TRICHOME-SPECIFIC WRKY 1 (AaGSW1), and AaORA, to upregulates their expression. These transcription factors then stimulate the expression of related biosynthetic genes and enhance the content of artemisinin (Hao et al., 2019; Fu et al., 2021b). HY5 can also affect the artemisinin biosynthesis by directly regulate the expression of biosynthetic genes in A. annua (Zhou et al., 2015). Phytochrome Interacting Factors (PIFs) also mediate the biosynthesis of SMs in many plant species. In C. roseus, under dark conditions, PIF1 binds to the promoters of deacetylvindoline-4-O-acetyltransferase (DAT) and GATA-type transcription factor gene GATA1, thus repressing the expression of target genes and decreasing the content of vindoline. Under red light, PIF1 is degraded, which stimulates the accumulation of vindoline (Liu et al., 2019). PIF3 upregulates the expression of ADS, CYP71AV1, artemisinic aldehyde Δ11(13) reductase (DBR2), and aldehyde dehydrogenase 1 (ALDH1), and dramatically increases the content of artemisinin under light in A. annua (Zhang et al., 2019c). AaMYB15 is reported as a negative regulator of artemisinin, it binds to the promoter of AaORA and inhibits the biosynthesis of artemisinin under light in A. annua (Wu et al., 2021).

As an indispensable environmental factor, light affects the contents and yields of almost all kinds of phytochemicals in medicinal plants. The responses of plants to light are species-specific, and the effects of light on SM biosynthesis are distinct among different species. Moderate UV-B and blue light irradiation improve the accumulation of phytochemicals in many medicinal plants. Compared with UV-B and blue light, red light promotes the growth and development of some medicinal plants and therefore is more efficient in enhancing the yield of target compounds. In nature, light intensity and photoperiod often act together with other environmental factors, either synergistically or antagonistically, to regulate SM biosynthesis in medicinal plants. The regulatory mechanisms underlying the effects of light intensity and photoperiod on SM biosynthesis have not yet been fully elucidated.

With the increasing demand for natural bioactive compounds, many environmentally controlled systems with artificial light sources have been used for the cultivation of medicinal plants. Light conditions optimal for SM production in different plant species have been determined, and light-responsive genes involved in the corresponding biosynthetic pathways have been characterized. However, the intact light signaling pathways in almost all medicinal plants remain unclear. Besides, the regulatory roles of light in plants are complex. Understanding how light systematically regulates the SM content and growth of medicinal plants, simultaneously affects the content and yield of target compounds is a challenge that should be tackled in the future.

SZ, DY, and YW conceptualized and designed the work, collected, analyzed, and interpreted the data, and drafted the manuscript. LZ and HZ collected the data and contributed to critical revision of the manuscript. LQ, YZ, and HZ approved the final version to be published. All authors contributed to the article and approved the submitted version.

This work was financially supported by the National Natural Science Foundation of China (31700257), Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (2060302), the Zhejiang Provincial Natural Science Foundation of China (LR21H280002).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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