Broussonetia: A Comprehensive Reference Article
1. Identity and Botanical Profile
1.1 Taxonomic Classification and Nomenclature
The Broussonetia genus (family Moraceae), recognized for its value in many Chinese traditional herbs, comprises three principal species of medicinal interest: Broussonetia papyrifera (L.) L'Hér. ex Vent. (abbreviated BP), Broussonetia kazinoki Siebold (BK), and Broussonetia luzonica (Blanco) Bureau (BL). Of these, B. papyrifera is by far the most widely studied and applied. The paper mulberry (Broussonetia papyrifera, syn. Morus papyrifera L.) is a species of flowering tree in the family Moraceae.
The genus name honors Pierre Auguste Marie Broussonet (1761–1807), a French physician, naturalist, and one-time professor of botany at Le Jardin des Plantes de Montpellier. The specific epithet derives from the Egyptian word papyrus (meaning paper) and the Latin word ferre (meaning to bear), in reference to the use of tree bark to make paper, and the common name reflects the long-established practice of using the tree's inner bark in East Asia to make paper, and in Polynesia to make barkcloth (Tapa cloth).
Common synonyms and vernacular names include: Morus papyrifera L.; Papyrius japonica Lam.; paper mulberry (English); chǔ (Chinese, 楮); kozo (Japanese); daknamu or dak (Korean); wauke (Hawaiian).
1.2 Botanical Description and Native Range
B. papyrifera is a deciduous shrub or small tree with a broad, spreading crown, usually growing up to 9 metres tall, though in a suitable climate it can reach 20 metres or more. Paper mulberry is dioecious (separate male and female trees). Young twigs are downy reddish-brown, gray bark matures over time to gray-brown with furrows, and the trees have a milky sap. The large, broad-oval, dull green leaves (to 8 inches long) have serrate margins and asymmetrically cordate bases; they are rough-textured above and densely tomentose beneath.
It is native to East and Southeast Asia, including mainland China, Hong Kong, India, Japan, Korea, Myanmar, and Taiwan. The paper mulberry was one of the most widely distributed crop species in prehistoric Oceania, occurring from continental East Asia to the Polynesian islands, with its broad distribution largely attributable to human-mediated dispersal during colonization of the islands of Near and Remote Oceania.
1.3 Plant Parts Used and Common Forms
B. papyrifera is a deciduous tree or shrub that grows naturally in the Asian and Pacific region in China, Thailand, and the USA; its roots, leaves, bark, and fruit are all used in traditional Chinese medicines. In the context of dietary supplementation and cosmetics, the parts most commonly processed into preparations include:
- Root bark: Solvent extracts (ethanolic, methanolic, chloroform-soluble fractions) widely used in in-vitro and in-vivo research; also the source of commercially relevant skin-lightening compounds.
- Leaves: Dried powders, water decoctions, and ethanolic extracts used in forage research, immunology studies, and anti-inflammatory research.
- Fruits: Used in traditional medicine as whole dried fruits or decoctions; also analyzed for antioxidant content in supplement contexts.
- Stem bark: Methanol and aqueous fractions investigated for anti-inflammatory properties.
A narrative review published in the journal Cosmetics (MDPI, 2022) summarized the chemical composition, biological activities, and applications of paper mulberry in cosmetics. Paper mulberry is widely applied in cosmetics for skin lightening and skin moisturizing purposes, and shows potential for application in hair care products due to its hair-nourishing effects.
2. Traditional and Historical Use
2.1 Traditional Chinese Medicine
B. papyrifera is a woody plant used in papermaking, traditional medicine, and pig feed in ancient China. In China, the leaves have been used to treat chronic prostatitis as a folk medicine, as well as for bleeding. The bark could be used for special recipes. The fruits have been confirmed in traditional practice to treat impotence and ophthalmic diseases, while the hematochrome (pigment) from the fruits was historically used as a foodstuff.
The roots of B. papyrifera have been used as a suppressant for edema in traditional Chinese medicine. The leaves are rich in essential trace elements such as copper, molybdenum, manganese, and iron, as well as various biologically active compounds, including amino acids, polysaccharides, proteins, flavonoids, phenylpropanoids, and other polyphenolic compounds; these compounds exhibit pharmacological effects described in traditional contexts as antioxidant, lipid-lowering, heat-clearing, detoxifying, blood-cooling, diuretic, and immunomodulatory.
Traditional uses recorded across various cultures include treatments for ocular disorders, gynaecological bleeding, and dysentery. The fruit of the plant is listed in the classical Chinese materia medica as chǔ shí (楮實), where it was prescribed for tonifying the kidneys, brightening the eyes, and strengthening the body. The bark (chǔ bái pí) was used for clearing heat and diuresis.
2.2 Korean and Japanese Traditional Medicine
B. kazinoki Siebold — called daknamu in Korean and closely related to the paper mulberry — occupies an important place in Korean medicine, where bark decoctions were used for conditions relating to poor vision, fatigue, and impotence. Japanese traditional practice similarly incorporated the bark and fruit of B. papyrifera in preparations for tonifying the reproductive system and improving vision.
2.3 Oceanic and Pacific Traditions
Wauke (B. papyrifera) is thought to have been carried in Polynesian canoes as root shoots during early voyaging, and the ancient practice of making bark cloth and bark paper likely began in Asia, where other species of Broussonetia are known. In the traditions of Tonga, Fiji, and Samoa, B. papyrifera, as a fibrous tree, was the main raw material used to make tapa cloth. Beyond its industrial role, the plant served as a food source in island societies: the leaves may be steamed as a food source in Polynesia.
2.4 Paper and Industrial Heritage
The paper mulberry was a significant fiber crop in the history of paper; known for its durability and longevity, it has been used for papermaking in China since sometime between the 2nd and 8th century. In Korea, the oldest existing block print in the world (c. 751 AD) was printed on hanji paper using its fibers. High-quality Korean hanji and Japanese washi are typically made from the inner bark, which is pounded and mixed with water to produce a paste and dried into sheets. Moreover, one of the Broussonetia species was used by Cai Lun to create paper, one of the four great inventions of ancient China.
3. Key Constituents and Active Compounds
3.1 Overall Phytochemical Profile
A comprehensive review identified 338 compounds isolated from BP, BK, and BL of the Broussonetia genus, including 144 flavonoids, 50 phenylpropanoids, 38 polyphenols, 35 alkaloids, 17 terpenoids, 5 steroids, and 49 other metabolites, indicating that flavonoids are the main constituent in the genus.
Paper mulberry consists of various components, including flavonoids, tannins, alkaloids, phenols, saponins, coumarins, glycosides, and polysaccharides, which possess a wide range of pharmacological properties.
3.2 Flavonoids
Flavonoids constitute the dominant chemical class. The major types of bioactive constituents reported from B. papyrifera are the prenylated flavonoids, which include compounds of the diphenylpropane, chalcone, flavan, flavanone, flavone, flavonol, and aurone classes. Key individual compounds include:
- Broussochalcone A and B: Prenylated chalcones with documented antioxidant and antiviral activity. Papyriflavonol A, present in B. papyrifera, is the most potent inhibitor of PLPro with an IC50 value of 3.7 µM. Other polyphenolic compounds from the same plant — including broussochalcone B, broussochalcone A, 4-hydroxyisolonchocarpin, papyriflavonol A, 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane, kazinol A, kazinol B, broussoflavan A, kazinol F, and kazinol J — were also more potent against PLPro than against 3CLPro.
- Kazinols (A, B, F, J, U): Prenylated flavan-type compounds predominantly isolated from the root bark of B. kazinoki and B. papyrifera.
- Broussofluorenones A, B, C: Novel benzofluorenone derivatives. Bioactivity-guided fractionation led to 12 polyphenols, including 4 chalcones, 4 flavans, 2 flavonols, and 2 novel species of benzofluorenones (11 and 12). Broussofluorenone A (11) and broussofluorenone B (12) emerged as new compounds possessing the very rare 5,11-dioxabenzo[b]fluoren-10-one skeleton.
- Papyriflavonol A: A prenylated flavonol with notable protease-inhibitory activity (see antiviral section).
3.3 Alkaloids
Of the approximately 30 species in the genus, only three have been subjected to previous phytochemical investigation. From over 100 compounds isolated, the major secondary metabolites reported thus far are alkaloids of the pyrrolidine type and several types of flavonoids. The 2022 comprehensive review identified 35 alkaloid compounds across the three studied species.
3.4 Phenylpropanoids and Polyphenols
Recent research has revealed various pharmacological properties of polyphenolic compounds from B. papyrifera, including antioxidant, blood glucose-lowering, antitumor, anti-inflammatory, and antibacterial effects. The plant contains approximately 25 types of polyphenolic compounds. Phenylpropanoids (50 identified compounds) include hydroxycinnamic acid derivatives and lignans.
3.5 Other Noteworthy Compounds
Phytochemical investigation of the branches of B. papyrifera resulted in the isolation of 31 compounds, including nine flavans, five diarylpropanoids, three steroids, two anthraquinones, two hydroxybenzoic acids, three terpenoids, six phenylpropanoids, and one heterocyclic compound. The leaves are also rich in essential trace elements such as copper, molybdenum, manganese, and iron, as well as amino acids, polysaccharides, and proteins.
4. Mechanisms of Action
4.1 Anti-inflammatory Mechanisms
Extensive phytochemical analysis of an ethanolic extract of branches and twigs of B. papyrifera led to the isolation of fourteen compounds, including a novel derivative named broussofluorenone C. These compounds were examined for anti-inflammatory activities in LPS-stimulated THP-1 cells; compounds 7–10 and 12 showed inhibitory effects on NF-κB/AP-1 activation, and compounds 7–9 were confirmed to suppress the secretion of both IL-1β and TNF-α in LPS-stimulated THP-1 cells more significantly than prednisone used as a positive control.
Results from in vitro experiments suggest that B. papyrifera stem bark has anti-inflammatory activity, specifically inhibiting NO production and proinflammatory cytokines in RAW 264.7 cells. In the psoriasis model, a leaf extract effectively alleviated imiquimod (IMQ)-induced psoriasis-like lesions, reduced the lesion area and severity index, decreased epidermal hyperplasia, ameliorated oxidative stress-induced changes in the levels of SOD and MDA, and reduced the levels of the inflammatory cytokines TNF-α and IL-17A.
4.2 Tyrosinase Inhibition and Melanogenesis
Paper mulberry extracts and their constituents showed strong inhibitory effects on the activity of tyrosinase enzyme and have been applied in cosmetics as skin-whitening ingredients. In 2019, Kim et al. conducted in vitro and in vivo experiments and demonstrated that kazinol U, a component found in the root bark of B. papyrifera, effectively suppresses the expression of MITF at a dosage of 0–20 µM. This inhibition leads to the activation of the AMPK and MAPK proteins, resulting in the reduction of tyrosinase, Tyrp1, and Tyrp2 and subsequent melanin formation. Additionally, kazinol U can maintain skin collagen content by neutralizing reactive oxygen species and preventing the activity of collagenase.
A flavonoid compound isolated from the root bark of B. papyrifera showed tyrosinase inhibition with an IC50 value of 9.29 µM, compared to the positive control kojic acid at 30.56 µM. Molecular docking indicated that hydrogen bond formation plays an important role in the ligand-enzyme complex.
4.3 α-Glucosidase and PTP1B Inhibition (Antidiabetic Mechanisms)
The organic extract of the roots of B. papyrifera showed extremely high α-glucosidase inhibitory activity with an IC50 of around 10 µg/mL. Subsequent bioactivity-guided fractionation of the chloroform extract led to the isolation of 12 polyphenols, including 4 chalcones, 4 flavans, 2 flavonols, and 2 novel benzofluorenones. The most potent inhibitor had an IC50 of 2.1 µM and Ki of 2.3 µM — inhibitory activity slightly higher than that of the established α-glucosidase inhibitor deoxynojirimycin (IC50 = 3.5 µM).
Broussochalcone, isolated from B. papyrifera, exhibited potent PTP1B inhibition with an IC50 of 21.5 µM. PTP1B is a negative regulator of insulin signaling, so its inhibition is considered a promising mechanism for improving insulin sensitivity.
4.4 Apoptosis and Anticancer Mechanisms
Investigations reveal that active compounds from B. papyrifera primarily function by promoting apoptosis, modulating the cell cycle, and inhibiting inflammatory and diabetic pathways. A flavanoid compound (compound 4) from the root bark exhibited cytotoxic activity against three cancer cell lines: NCI-H1975 (non-small cell lung cancer), HepG2 (hepatocellular carcinoma), and MCF-7 (breast cancer), with structure-activity relationships established for the broader flavonoid series.
4.5 Antiviral Mechanisms
Papyriflavonol A, present in B. papyrifera, is the most potent inhibitor of PLPro (a SARS-CoV-related protease), with an IC50 value of 3.7 µM. These data emerge from in vitro screening studies and have not yet been translated to clinical antiviral applications.
4.6 Antioxidant Mechanisms
In the cellular antioxidant activity (CAA) assay, one of the isolated B. papyrifera compounds exhibited the greatest antioxidant effect. In fruit extracts, the antioxidant activity of different extracts was positively associated with their total phenolic content.
5. Scientific Evidence by Area of Use
5.1 Skin Lightening and Anti-Pigmentation
Evidence summary: This is the most clinically relevant and commercially developed application of Broussonetia. Paper mulberry (B. papyrifera) is one of the most common skin-lightening agents in the beauty industry due to its strong anti-tyrosinase activity. Paper mulberry extract comes from the roots of the B. papyrifera tree and functions by inhibiting tyrosinase activity. It is widely used in South Africa and Europe as an alternative skin-lightening ingredient.
The safety of paper mulberry for topical application was proven in clinical studies. However, the volume of published, peer-reviewed clinical trial data in this area remains limited, and most mechanistic insight derives from cell-based assays and in vivo animal studies.
Evidence strength: In vitro and some in vivo evidence is strong; controlled human clinical trial data specific to Broussonetia extracts alone (as opposed to multi-ingredient cosmetic formulations) are limited in the published literature.
5.2 Anti-inflammatory Activity
Preclinical evidence: Multiple in vitro and animal studies support anti-inflammatory effects. B. papyrifera is described in traditional Chinese medicine as exhibiting significant therapeutic effect on psoriasis due to its anti-inflammatory and antioxidant properties. In a mouse model, a leaf extract (PLE) effectively alleviated imiquimod-induced psoriasis-like lesions, reduced psoriasis lesion area and severity index, decreased epidermal hyperplasia, ameliorated oxidative stress (SOD and MDA levels), and reduced inflammatory cytokines TNF-α and IL-17A.
In a separate study, the effects of an ethanolic extract of BP leaves (BPE, 200 mg/kg) on mitigating 2% dextran sodium sulfate (DSS)-induced intestinal inflammation in mice were evaluated; BPE is rich in flavonoids, polyphenols, and polysaccharides, and displays potent antioxidant and antibacterial activities against pathogenic strains such as Clostridium perfringens, Salmonella Typhimurium, and Salmonella enterica subsp. enterica in vitro.
Evidence strength: Predominantly preclinical (in vitro cell models and animal models). No registered human clinical trials for inflammatory diseases are currently indexed in the published literature for Broussonetia extracts as sole interventions.
5.3 Antidiabetic Effects
Preclinical evidence: Enzyme inhibition studies are among the most rigorously characterized activities. The organic extract of the roots of B. papyrifera showed extremely high α-glucosidase inhibitory activity with an IC50 of around 10 µg/mL. Individual purified compounds exceeded the activity of established pharmacological comparators in vitro. Broussochalcone, isolated from B. papyrifera, exhibited potent PTP1B inhibition with an IC50 of 21.5 µM.
Evidence strength: Currently limited to in vitro enzyme assays and, to a lesser extent, animal models. No human clinical trials evaluating glycemic outcomes of Broussonetia preparations have been identified in the indexed literature.
5.4 Antitumor / Cytotoxic Activity
A variety of pharmacological activities have been demonstrated in in vivo or in vitro assays, including anti-tumor properties. Cytotoxic work has demonstrated activity against multiple cancer cell lines in laboratory settings. One flavanoid compound from root bark exhibited cytotoxic activity against NCI-H1975, HepG2, and MCF-7 cell lines.
Evidence strength: Strictly in vitro (cell line studies) and preliminary. No human cancer clinical trials involving Broussonetia preparations have been published. These findings cannot be extrapolated to clinical antitumor efficacy.
5.5 Antiviral Activity
Papyriflavonol A, present in B. papyrifera, is the most potent inhibitor of PLPro among tested polyphenols, with an IC50 value of 3.7 µM. The study of Broussonetia compounds as coronavirus protease inhibitors represents an emerging but exclusively in vitro body of work.
Evidence strength: In vitro only. No human antiviral clinical data exist.
5.6 Antioxidant Properties
The changes in total phenolic content and antioxidant capacity in B. papyrifera from four different regions were assessed; the antioxidant activity of different extracts was positively associated with their total phenolic content. These results suggest that the fruit could be used in dietary supplement preparations, or as a food additive, for nutritional gain or to prevent oxidation in food products.
Evidence strength: Primarily in vitro (DPPH, ABTS, CAA assays) with supportive in vivo animal data. No human trials specifically assessing antioxidant biomarker changes have been published for Broussonetia preparations.
5.7 Antibacterial Activity
BPE (ethanolic extract of B. papyrifera leaves) displays potent antioxidant and antibacterial activities against pathogenic strains such as Clostridium perfringens, Salmonella Typhimurium, and Salmonella enterica subsp. enterica in vitro. The plant exhibits extensive pharmacological properties, including antimicrobial activity; the Minimum Inhibitory Concentration (MIC) for antimicrobial activity has been reported as 10.25 µg/ml.
Evidence strength: In vitro only. No human clinical data.
5.8 Anti-atopic Dermatitis Activity
Phytochemical investigation of the branches of B. papyrifera resulted in the isolation of 31 compounds; among them, seven compounds were isolated from the Moraceae family for the first time. Evaluation of the flavan and diarylpropanoid compounds for anti-atopic dermatitis activity demonstrated that eight compounds inhibited IL-13 secretion in HaCaT cells.
Evidence strength: In vitro cell assay. No human clinical trials.
5.9 Broader Activities Noted in Reviews
Apart from its anti-tyrosinase activity, paper mulberry and its compounds have exhibited anti-inflammatory, antioxidant, antimicrobial, antiviral, anticancer, antidiabetic, anticholinesterase, antigout, antinociceptive, and hepatoprotective effects in preclinical models.
6. Dosages Reported in Studies
Because human clinical trial data are absent or very limited, the dosages below are taken directly from the preclinical study methods cited in peer-reviewed sources:
- Ethanolic leaf extract (BPE), mouse intestinal inflammation model: 200 mg/kg body weight in mice evaluated against 2% DSS-induced intestinal inflammation.
- α-Glucosidase inhibitory assay (root extract): IC50 of approximately 10 µg/mL in the organic root extract, with isolated compound IC50 values as low as 2.1 µM.
- Tyrosinase inhibition (isolated compound): IC50 of 9.29 µM, compared to kojic acid (positive control) at 30.56 µM.
- Melanogenesis suppression (kazinol U, in vitro): Effective suppression of MITF expression at a dosage of 0–20 µM.
- PTP1B inhibition (broussochalcone): IC50 of 21.5 µM.
- Antiviral (papyriflavonol A against PLPro): IC50 value of 3.7 µM.
- Anti-inflammatory NF-κB/AP-1 inhibition: Cells were treated with 100 µg/mL fractions of stem bark methanol extract, followed by LPS stimulation (100 ng/mL) for 24 hours in RAW 264.7 macrophage assays.
No established human therapeutic dose ranges have been defined in published clinical literature for any Broussonetia preparation taken orally as a dietary supplement.
7. Body Systems and Health Areas Associated with Broussonetia
- Integumentary system (skin): Skin lightening, depigmentation, anti-wrinkle, moisturizing, atopic dermatitis, psoriasis, wound healing.
- Metabolic / endocrine system: Blood glucose regulation via α-glucosidase and PTP1B inhibition; lipid-lowering activity noted in leaf extracts.
- Immune system: Modulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-17A); NF-κB pathway suppression; immunomodulatory effects in cyclophosphamide-immunosuppressed animal models.
- Gastrointestinal system: Antibacterial activity against intestinal pathogens; anti-colitis effects in murine DSS models.
- Reproductive and urological system: Traditional use for impotence, prostatitis, and diuresis.
- Ocular system: Traditional use for ophthalmic diseases and "brightening the eyes."
- Oncology (preclinical only): Cytotoxic activity against lung, liver, and breast cancer cell lines in vitro.
- Antiviral (preclinical only): Enzyme inhibition relevant to coronavirus proteases in vitro.
8. Safety Considerations
8.1 Pollen Allergenicity
The most well-documented safety concern related to B. papyrifera is the allergenic potential of its pollen, which is distinct from the plant extracts used medicinally or cosmetically. B. papyrifera is a tree-producing allergenic pollen that grows in varied climatic conditions worldwide and causes pollen allergies in susceptible humans. In a Taiwan-based study, after excluding participants with positive responses to a negative control, 38.4% of 30 recruited volunteers were determined to be sensitive to B. papyrifera pollen extract. The three-day lagged concentration of B. papyrifera pollen exhibited the highest risk of daily asthma visits (RR = 1.166, 95% CI: 1.014–1.341) and allergic rhinitis visits (RR = 1.119, 95% CI: 0.916–1.367).
B. papyrifera is anemophilous (wind-pollinated), and its pollen is allergenic. Skin prick test (SPT) and ELISA analyses identified 33-kDa and 40-kDa proteins as putative allergens that may elicit clinical responses in humans. The tree pollen is reported to cause urticaria and severe respiratory symptoms.
LC-MS/MS analysis of the pollen detected four lipids that can potentially stimulate inflammatory responses. Pollen protein immunoblotting studies identified a putative 15 kDa novel allergen and verified previously known 40 kDa, 33 kDa, and 10 kDa allergens.
8.2 Topical Safety
A skin-whitening composition containing Broussonetia extracts has been described as having excellent effects on the inhibition of tyrosinase activity and melanin production, with excellent skin safety. The safety of paper mulberry for topical application was proven in clinical studies. Notably, published clinical safety data specifically evaluating paper mulberry extract in isolation are scarce in the peer-reviewed literature; most safety assertions arise from formulation-level testing.
8.3 Overall Evidence Gaps and Limitations
Despite the extensive bioactivities that have been identified, the targeted clinical trials that are normally used to evaluate safety and effectiveness for humans are currently absent. The addition of clinical trials would be a more comprehensive and scientific way to ascertain the medical role of the Broussonetia genus.
A published review emphasizes the need for further clinical trials and toxicity studies on this species. The heavy metal absorption capacity of the plant is also relevant: B. papyrifera's phytoremediation potential is notable, as it absorbs heavy metals like manganese effectively, which raises a consideration for plant material sourced from contaminated environments, though this is a concern at the agricultural sourcing level rather than an intrinsic pharmacological risk.
Some studies of the Broussonetia genus are currently limited: of the 338 compounds isolated, only 5 steroids and 17 terpenoids are represented, suggesting that large chemical subclasses remain under-characterized.
References
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