Paris polyphylla

Paris polyphylla (Rhizoma Paridis / Chonglou): A Comprehensive Reference

1. Identity and Botanical Description

Scientific name: Paris polyphylla Sm. (Smith, 1804). The species belongs to the family Melanthiaceae (formerly classified within Liliaceae and Trilliaceae in older literature). The plant is primarily found in southern China and other regions of Asia, particularly Vietnam.

Paris polyphylla Sm. is a Himalayan ethnomedicinal plant at risk of extinction, used in pharmaceutical production and in traditional systems such as Ayurveda and Chinese medicine to treat various illnesses. It is a perennial herb with various properties including clearing away heat, detoxification, detumescence, pain relief, and calming convulsion, widely used in the treatment of furuncles, carbuncles, sore throat, snakebite, traumatic pain, and convulsion.

The plants of genus Paris, containing about 33 species and 15 varieties, are mainly distributed in southwest China (Yunnan, Sichuan, and Guizhou provinces). It is mainly distributed in the tropics of Europe and Asia, and in China is found principally in Sichuan Province, Guizhou Province, Yunnan Province, Guangxi Province, Guangdong Province, Jiangxi Province, and Fujian Province. Through years of cultivation and evolution, this herb has been widely distributed in Asian regions such as India, China, Bhutan, Laos, Myanmar, Nepal, Thailand, and Vietnam.

The two varieties officially recognized as medicinal drug sources are Paris polyphylla var. yunnanensis (Franch.) Hand.-Mazz. and Paris polyphylla var. chinensis (Franch.) Hara. The dried rhizomes of P. polyphylla var. yunnanensis and Paris polyphylla Smith var. chinensis are recorded in the Chinese Pharmacopoeia (2020 version), which describes their effects of clearing heat and detoxifying, reducing swelling and pain, and cooling the liver and calming convulsions.

Common Names and Synonyms

The plant is known as kalchung (Tamil), trọng lâu nhiều lá (Vietnamese), thoksampa (Sarchop), Chonglou (Pinyin transliteration), Paris root (English), and Rhizoma Paridis (pharmacopoeial name); in China, the term chonglou is widely used. In the Flora of China, the name qi ye yi zhi hua (七叶一枝花) is used for P. polyphylla. In Nepal and Sikkim Himalaya, it is locally called "Satuwa" in Nepali and "Tuk-tok-bee-sungtee" in Lepcha.

Pharmacopoeial Status

The plant was first reported in the Shennong Materia Medica Classic, first named Chonglou in the Dian Nan Ben Cao and later in Li Shizhen's Compendium of Materia Medica, and was listed in the Chinese Pharmacopoeia for the first time in 1985. The dried rhizomes of these plants (Rhizoma Paridis) are an indispensable ingredient of seven preparations recorded in the Chinese Pharmacopoeia (2020).

Conservation Status

The IUCN Red List has designated it as "vulnerable" due to a decline in wild population caused by over-exploitation, habitat degradation, and illegal collection for trade and traditional use. It takes 7–8 years for the rhizomes to reach drug standards, and excessive excavation has caused wild resources to face severe shortages.

Common Preparations and Forms

Paris polyphylla is commonly administered as decoctions or as powdered Rhizoma Paridis. In folk medicine in northwest Yunnan, commonly employed processing methods include use in both dry and fresh forms, while special processing methods such as processing in wine and honey, steaming, and foil-packet boiling are also practiced. Extracts of Paris polyphylla rhizomes are prepared using solvents ranging from polar (aqueous, alcoholic) to nonpolar (petroleum ether), and demonstrate broad bioactivity at the extract level, exhibiting antioxidant, antimicrobial, and antitumor effects primarily attributable to their Paris polyphylla saponin (PPS) content.

Paris species is used to produce patent medicines such as "Yunnan Baiyao" and "Gongxue Ning," demonstrating significant therapeutic effects in hemostasis, anti-inflammation, and the treatment of injuries from falls and impacts. One of the seven pharmacopoeial preparations is "Qizhen capsule" (芪珍胶囊), which has traditionally served as an adjuvant therapy for lung, breast, and gastric cancer.

2. Traditional and Historical Use

Traditional Chinese Medicine (TCM)

For over 2,000 years, Paris polyphylla has been used as an important natural medicinal plant in China to treat infection, inflammation, and cancer, and was first reported in the Shennong Materia Medica Classic. Its medicinal properties are well-documented in classical texts of TCM, such as the Shennong Bencao Jing; Rhizoma Paridis is particularly recognized for its effects in clearing heat, detoxifying the body, reducing swelling, alleviating pain, cooling the blood, and stopping bleeding.

Rhizoma Paridis was first recorded in the Shennong Bencao Jing under the name Zao Xiu, and in the Ben Cao Gang Mu was listed by Li Shizhen. In traditional Chinese medicine, it is used as a component of topical medicaments indicated for treatment of boils, carbuncles, sore throat, venomous snake bite, and traumatic pain.

Its dried rhizomes are valued for their bitter taste, cool nature, and affinity to the liver meridian, exhibiting efficacy in clearing heat, detoxifying, reducing swelling, alleviating pain, and calming convulsions.

An ethnobotanical investigation in northwest Yunnan conducted in 2023 involved semi-structured interviews with 14 highly regarded folk doctors. The researchers identified twenty-three traditional treatments and thirty pairing herbs used with P. polyphylla var. yunnanensis in therapy; results indicated that PPvY and its associated formulas were primarily used for treating cancer and inflammation and for clearing heat and detoxifying. More broadly, P. polyphylla var. yunnanensis is used as a botanical drug by eight ethnic minorities in China, constituting one ingredient from 62 recipes effective for the main treatment of multiple human diseases and afflictions, including tumors, skin injury, poisoning, virus infections, and diseases affecting the respiratory, digestive, urogenital, and musculoskeletal systems.

Ayurvedic and Himalayan Traditions

Paris polyphylla Sm. is an important medicinal plant used to treat a variety of diseases through traditional medicine systems such as Ayurveda, Tibetan traditional medicines, Chinese traditional medicines, and others around the world. In traditional medicine, the roots are used as analgesic, antiphlogistic, antipyretic, antispasmodic, antitussive, depurative, febrifuge, and narcotic. In the Indian Himalayan Region, P. polyphylla is used against burn, cut or injury, diarrhea, dysentery, fever, gastritis, skin diseases, stomach pain, and wounds.

It is considered helpful in the treatment of heart disease, asthma, and bronchitis. Rhizomes are used as anthelmintic and tonic by the local inhabitants of Garhwal, and root powder is used in ethnopediatrics for diarrhea in this region.

Tibetan Traditional Medicine

In Tibetan and related traditions, prepared Rhizoma Paridis has remarkable therapeutic effects on fractures, parotitis, hemostasis, snake bite, and abscess in clinical use for thousands of years. Historically, it has been used for centuries to treat a variety of conditions, including mumps, bleeding disorders, snake bites, fractures, and abscesses.

Traditional Preparations

The dried rhizomes of P. polyphylla, P. polyphylla var. chinensis, and P. polyphylla var. yunnanensis were used to treat wound, bleeding, and stomachache in folk medicine. In traditional and folk uses, Paris plants were commonly used to treat furuncle and phyma, ulcer, snake bite, insect sting, gastric ulcer, and bleeding knife wound.

3. Key Constituents and Active Compounds

More than 320 chemical components have been isolated from genus Paris since 2020, including steroidal saponins, C-21 steroids, phytosterols, insect hormones, pentacyclic triterpenes, flavonoids, and other compounds. Paris saponins or steroidal saponins are the main bioactive chemical constituents from this plant, accounting for more than 80% of the total compounds.

Steroidal Saponins (Polyphyllins)

The primary and most pharmacologically important class of compounds in Paris polyphylla is the steroidal saponins, collectively referred to as polyphyllins or Paris saponins. The main active ingredients of Rhizoma Paridis — including total saponins, polyphyllin I, polyphyllin II, polyphyllin VI, and polyphyllin VII — have shown strong antitumor activities in various cancers, such as breast cancer, lung cancer, colorectal cancer, hepatocellular carcinoma (HCC), and gastric cancer. Rhizoma Paridis also contains low concentrations of other active ingredients with antitumor effects, such as polyphyllin E, polyphyllin H, Paris polyphylla-22, gracillin, and formosanin-C.

Over 130 steroidal saponins have been isolated from genus Paris, most of which were from P. polyphylla var. yunnanensis, and a few compounds were isolated from P. polyphylla var. chinensis, besides recently reported unknown constituents from the aerial parts.

Other Major Compound Classes

Secondary metabolites such as alkaloids, flavonoids, saponins, carbohydrates, glycosides, cardiac glycosides, terpenoids, sterols, quinones, phenols, and tannins have been detected by phytochemical screening. From the aerial parts of Paris polyphylla var. chinensis, ten compounds were isolated and identified including β-sitosterol, ergosta-7,22-dien-3-one, β-ecdysone, kaempferol, daucosterol, luteolin, calonysterone, luteolin-7-O-glucoside, quercetin, and 3β,5α,9α-trihydroxyergosta-7,22-dien-6-one.

Paris spp. mainly contain ecdysteroids such as β-ecdysone, calonysterone, β-ecdysterone, and 5-hydroxyabutastorone, with β-ecdysone distributed in various members of the genus Paris including P. polyphylla var. yunnanensis, P. polyphylla var. japonica, and P. fargesii.

In leaves, several compounds have been preliminarily identified from different fractions, including 36 steroidal saponins, 11 flavonoids, 10 ceramides, 8 lipids, 6 organic acids, and 8 other compounds.

Notable Individual Compounds and Their Structural Features

• Polyphyllin I (Paris Saponin I): A diosgenyl saponin with antitumor, anti-inflammatory, analgesic, antibacterial, antiviral, and hemostatic activities.
• Polyphyllin II (Paris Saponin II): Paris Saponin II has been shown to have anticancer activity against several cancer cell lines through the pro-apoptotic pathway.
• Polyphyllin D (Gracillin / 17-Hydroxygracillin): A pennogenyl saponin. The gracillin component of P. polyphylla rhizome can inhibit the growth of six types of human tumor cells: lung cancer (A-549), breast cancer (MCF-7), colon cancer (HT-29), kidney cancer (A-496), pancreatic cancer (PACA-2), and prostate cancer (PC-3).
• Polyphyllin VI: Polyphyllin VI is a main active saponin showing antitumor activity against lung cancer A549 and NCI-H1299 cell lines, breast cancer MCF-7 and MDA-MB-231 cell lines, and hepatocellular carcinoma HepG2 cell line.
• Polyphyllin VII: A pennogenyl saponin from P. polyphylla that has been found to exert strong anticancer activity.
• Formosanin C: A steroidal saponin with antitumor and immunomodulatory properties.
• Diosgenin: Study of the chemical components of Paris can be traced back to the 1960s, when Huang et al. isolated diosgenin from rhizomes of P. polyphylla var. yunnanensis (Huang and Zhou, 1962).

Steroidal saponins are the primary active compounds in Rhizoma Paridis, renowned for their diverse biological activities; their chemical structure, which resembles that of steroid hormones, allows them to exert various pharmacological effects in the body.

4. Mechanisms of Action

Reactive Oxygen Species (ROS) Modulation and Anticancer Signaling

Paris polyphylla saponins (PPS) modulate oxidative stress through precision targeting of ROS-associated signaling pathways, thereby inducing apoptosis, cell cycle arrest, autophagy, and ferroptosis; these mechanisms collectively suppress tumor growth, metastasis, and angiogenesis, while concurrently mitigating inflammatory responses.

Notably, PPS potentiates the efficacy of chemotherapeutic agents by reversing multidrug resistance in refractory cancer cells; the bioactive constituents polyphyllin and polyphyllinositol exhibit potent antitumor activity in preclinical models.

Apoptosis Pathways

PPS demonstrate potent pro-apoptotic activity across multiple cancer cell lineages; they orchestrate apoptotic signaling via dual regulatory mechanisms, modulating intracellular ROS homeostasis through both intrinsic (mitochondrial) and extrinsic (death receptor-mediated) pathways, with the mitochondrial pathway being the primary mechanism through which PPS induce apoptosis.

Mechanistically, polyphyllin D dissipates the mitochondrial membrane potential, induces downregulation of anti-apoptotic Bcl-2 expression and upregulation of pro-apoptotic Bax expression, and activates caspase-9, suggesting that polyphyllin D elicits apoptosis through mitochondrial dysfunction.

Cell Cycle Arrest and Autophagy

Research has found that steroidal saponins can combat cancer through multiple molecular mechanisms, including inducing apoptosis in cancer cells, blocking the cell cycle, and inhibiting the migration and invasion of cancer cells.

Neuroprotective Mechanisms

Polyphyllins demonstrate potent neuroprotective activities through anti-inflammatory, antioxidant, and autophagy-modulating mechanisms; PP-II interrupts the KEAP1-NRF2 interaction, activating antioxidant gene expression, while PP-I induces mitophagy via the PINK1-Parkin pathway, and PP-VII modulates neuroinflammation through activation of the cGAS-STING axis, actions that collectively protect neurons, preserve mitochondrial function, and reduce pathological cascades.

Antioxidant Mechanism

The phenolic hydroxyl groups within saponin structures contribute to antioxidant effects by scavenging free radicals and chelating redox-active metal ions (e.g., Fe²⁺, Cu²⁺), thereby inhibiting lipid peroxidation and hydroxyl radical generation.

Multitarget Pharmacology

Pharmacological studies have systematically characterized PPS as multifunctional agents with anti-inflammatory, analgesic, immunomodulatory, and antitumor activities, along with hemostatic, antimicrobial, and detoxifying properties.

5. Scientific Evidence by Area of Use

5.1 Oncology (Antitumor Activity)

Preclinical Evidence — Breast Cancer

Polyphyllin D was studied for its anticancer effects in breast cancer; treatment of MCF-7 and MDA-MB-231 cells resulted in inhibition of viability and induction of apoptosis in a dose-dependent manner, with an IC₅₀ of 5 μM and 2.5 μM, respectively, after 48 hours of incubation. An in vivo study demonstrated that daily administration of polyphyllin D (2.73 mg/kg body weight) through intravenous injection for ten days in nude mice bearing MCF-7 cells effectively reduced tumor growth by 50% in terms of tumor weight and size, with no significant toxicity in the heart and liver of the host. These findings are in vitro and in vivo (animal model) only; no human clinical trials have evaluated polyphyllin D monotherapy in breast cancer.

Preclinical Evidence — Colorectal Cancer

Paris polyphylla extract (PPE) activated caspase-3 in HCT-116 colorectal cells in a dose-dependent manner, ultimately leading to apoptosis; a synergic effect of P. polyphylla extract with 5-fluorouracil (5FU) and oxaliplatin in the human hepatoma cell line has also been reported. PPE (2, 3, 5, and 7 μg/mL) acts synergistically with 5FU (130 μg/mL); similarly, PPE (3, 5, and 7 μg/mL) with cisplatin (300 μg/mL) showed synergistic combination in HCT-116. All evidence is preclinical (in vitro).

Preclinical Evidence — Osteosarcoma

Polyphyllin VI was investigated for its antitumor effect against human osteosarcoma cells (U2OS); U2OS cell lines were used to determine the antiproliferative effect by CCK8 assay, cell cycle was analyzed by flow cytometry, and apoptosis was determined by Annexin V-APC/7-AAD detection. Involvement of H₂O₂ formation and ROS/JNK activation in the autophagic pathway was demonstrated, revealing the multifunctionality of Polyphyllin VI via autophagy and apoptosis in osteosarcoma cells.

Preclinical Evidence — Hepatocellular Carcinoma

Paris polyphylla is an oriental folk medicine with anticancer activities both in vivo and in vitro; Polyphyllin VII (PP7), a pennogenyl saponin, has been found to exert strong anticancer activity against human liver cancer cells.

Summary of Oncological Evidence Strength: Rhizoma paridis total saponins have significant anti-tumor effects on various solid tumors such as breast cancer, colorectal cancer, and glioma; the mechanism of action may involve multiple aspects, including directly exerting toxicity on tumor cells, modulating the body's immune response, inhibiting the formation of tumor blood vessels, and reducing the resistance of tumor cells to therapeutic drugs. However, future research and development of Rhizoma Paridis should not only focus on enhancing its antitumor activities and clarifying its antitumor mechanism but also on reducing its toxicity and side effects; more clinical studies of the therapeutic safety of Rhizoma Paridis should be carried out to ensure the safety and efficacy of this TCM medicine and its active ingredients in anticancer therapy. Overall, the oncological evidence base consists almost entirely of preclinical (cell-line and animal model) data; robust human clinical trials are absent.

5.2 Anti-inflammatory and Analgesic Activity

Paridis Rhizoma is employed for treating fractures, sore throat, and snake bite, and its primary active constituents, steroidal saponins, have significant bioactivities including antitumor, anti-inflammatory, and hemostatic properties. Polyphyllin I (PPI), polyphyllin II (PPII), polyphyllin VII (PPVII), polyphyllin H (PPH), and polyphyllin D are known to exert antitumor, anti-inflammatory, analgesic, antibacterial, antiviral, hemostatic, immune, and other therapeutic effects.

Evidence in this area is derived primarily from preclinical pharmacological studies and ethnopharmacological reports; controlled human trials evaluating Paris polyphylla specifically for inflammation or pain are not established in the peer-reviewed literature reviewed here.

5.3 Hemostatic Activity

Contemporary pharmacological research demonstrates that steroidal saponins from Paris species typically possess anticancer, hemostatic, anti-inflammation, antimicrobial, antifertility, and immunomodulation effects. Polyphyllin H enhances blood clotting in the body and was also shown to treat acute myelogenous leukemia. The hemostatic use of Rhizoma Paridis is one of its oldest and most widely documented traditional applications and is supported by in vitro and preclinical data, though systematic clinical trials are lacking.

5.4 Antimicrobial Activity

Antioxidant, anticancer, anti-leishmaniasis, antibacterial, antifungal, anthelmintic, antityrosinase, and antiviral effects of extracts and pure compounds have been demonstrated in vivo and in vitro. In recent years, an increasing number of steroidal saponins with antitumor and antimicrobial activities have been continuously reported from Paridis Rhizoma. These findings remain at the in vitro and preclinical stage.

5.5 Neuroprotective Potential

Polyphyllins are bioactive steroidal saponins long employed in TCM for detoxification, inflammation control, and pain relief; growing evidence supports their neuroprotective efficacy, especially in the context of neurodegenerative diseases (NDs), where inflammation, oxidative stress, and dysregulated cell death are central to disease progression. However, poor solubility and limited blood-brain barrier permeability remain key translational barriers; the promising therapeutic effects of polyphyllins in ND models align with their historical use in TCM but have yet to be translated into human trials.

5.6 Antifertility and Gynaecological Applications

An important aspect responsible for increasing interest in genus Paris is the use of antifertility, non-hormonal contraceptives by women. Paris polyphylla Sm. (Chonglou) is recorded in the Shennong Herbal Classic for its ability to relieve heat, remove toxic material, produce detumescence, and exert analgesic effects; "Gongxuening capsules," which are commonly used in the clinical treatment of adenomyosis, are developed from Paris polyphylla Sm. The evidence base for antifertility applications largely consists of traditional use records and preliminary preclinical studies; large-scale human trials are not yet established.

5.7 Immunomodulatory Activity

The P. polyphylla rhizome has anti-bacterial, anti-inflammatory, hemostatic, and immunomodulatory effects; the pharmacopeia records that its rhizome is the main source of Chonglou, with chemical composition mainly including steroidal saponins; it exerts anti-cancer effects by inducing apoptosis, promoting anti-angiogenesis, and synergizing with chemotherapeutic drugs.

6. Body Systems and Health Areas Associated with Paris polyphylla

• Oncology / Cancer Biology: Breast, lung, colorectal, hepatocellular, gastric, osteosarcoma, prostate, melanoma, and nasopharyngeal cancers (preclinical evidence across all types).
• Immune System: Immunomodulation, immunostimulatory effects on natural killer cells and macrophages (preclinical).
• Hematology: Hemostasis, platelet aggregation support, treatment of bleeding disorders (traditional and preclinical).
• Nervous System: Neuroprotection in models of neurodegeneration; anticonvulsant use in TCM tradition (preclinical and traditional).
• Digestive System: Traditional use for gastric ulcer, stomachache, diarrhea, dysentery; preclinical activity in digestive tract cancers.
• Respiratory System: Traditional use for sore throat, cough, asthma, and bronchitis (traditional evidence).
• Dermatology / External Use: Traditional topical application for boils, carbuncles, furuncles, wounds, burns, and snakebite.
• Reproductive / Gynaecology: Antifertility, adenomyosis treatment (traditional and preliminary preclinical).
• Musculoskeletal: Traumatic injury, fractures, pain relief (traditional evidence).

7. Dosage Forms and Reported Dosages

In TCM, the dried rhizomes are valued for their bitter taste, cool nature, and affinity to the liver meridian. The following dosages are reported specifically in the cited scientific literature:

• Polyphyllin D in vivo (mouse model): Daily administration of polyphyllin D at 2.73 mg/kg body weight, administered via intravenous injection for ten days in nude mice bearing MCF-7 breast cancer cells, effectively reduced tumor growth by 50%.
• Polyphyllin II in vivo (intestinal toxicity assessment): Polyphyllin II had no obvious toxicity at a dose of 20 mg/kg in vivo.
• Rhizoma Paridis saponins long-term toxicity (rat model): Long-term toxicity studies of Rhizoma Paridis saponins have shown significant chronic toxicity, particularly affecting the liver and gastrointestinal systems; high doses (350 mg/kg) in rats led to weight loss and reduced food and water intake, indicating impaired gastrointestinal function.
• Rhizoma Paridis saponins sub-chronic administration (rat model): The latter was administered 200 mg/kg of Rhizoma Paridis saponins (1/8 LD50) orally every day for 45 days.
• Traditional/Pharmacopoeial context: The Chinese Pharmacopoeia clearly describes its hypotoxicity and reminds the patient and doctor to note the possible problems of orally ingesting Rhizoma Paridis and its drug preparations in high doses or over prolonged periods, and when taken with other liver-damaging drugs.

No established and validated human clinical dosing regimens specific to isolated polyphyllin constituents have been identified in the peer-reviewed literature. All dosages cited above are from preclinical (animal) models or in vitro experiments.

8. Safety Considerations and Toxicity

General Toxicity Profile

Despite its significant medicinal benefits, the potential toxicity of Rhizoma Paridis must not be overlooked; research has identified several chemical compounds, including steroidal saponins and alkaloids, which contribute to its therapeutic effects but may also trigger toxic reactions.

Hepatotoxicity

Toxicity evaluation studies have suggested that Rhizoma Paridis has slight liver toxicity. 90-day administration of Rhizoma Paridis saponins (RPS) in rats induced liver injury; oral administration of RPS possessed certain liver toxicity in SD rats, with NMR and GC/MS data indicating that RPS inhibited the oxidation of fatty acids, glycolysis, and the TCA cycle pathway, and disturbed glycine, serine, and threonine metabolism.

Prolonged exposure caused liver cell damage, oxidative stress, and elevated liver markers (ALT and AST), with the high-dose group showing the most severe effects; the medium and low doses (50 and 100 mg/kg) also caused some liver damage.

Relevant studies have shown that Rhizoma Paridis is hepatotoxic; polyphyllin I, II, VI, and VII were cytotoxic to both hepatocytes HL-7702 and HepaRG cells, and furthermore Polyphyllin I, which can induce HepG2 cells' apoptosis through intracellular and extracellular apoptotic pathways, was proved to be the most cytotoxic among them.

Pathological examinations primarily revealed inflammatory changes in the liver and heart in several cases; notably, wild varieties elicited more pronounced organ damage than cultivated ones; comprehensive network toxicology and transcriptomic analyses revealed that P. polyphylla intervention disrupted hepatic metabolic homeostasis through pathways that impair mitochondrial structure and function, while simultaneously activating inflammatory response pathways and promoting hepatocyte apoptosis.

Gastrointestinal Toxicity

Animal studies have shown that Rhizoma Paridis causes side effects such as nausea, vomiting, diarrhea, and even hemolysis. Gastrointestinal toxicity induced by Rhizoma Paridis is a significant concern in its clinical application; long-term toxicity studies of Rhizoma Paridis saponins have shown significant chronic toxicity, particularly affecting the liver and gastrointestinal systems; high doses (350 mg/kg) in rats led to weight loss, reduced food and water intake, indicating impaired gastrointestinal function.

Hemolytic Toxicity

The mechanism underlying polyphyllin D-induced hemolysis begins with the activation of calcium channels on the red blood cell (RBC) membrane, leading to an increase in intracellular calcium ion concentration; this calcium influx promotes the externalization of phosphatidylserine, cell shrinkage, and the activation of caspase-3, hallmark features of apoptosis (eryptosis); in addition, polyphyllin D directly affects the RBC membrane, increasing its permeability and facilitating the exchange of calcium ions. Due to its strong hemolytic and cytotoxic effects, polyphyllin D's clinical application is limited; future research should focus on developing more efficient drug delivery systems to mitigate its toxicity to RBCs while preserving its anticancer potential.

Dose-Dependent Toxicity and Chinese Pharmacopoeia Warnings

Clinical research regarding adverse reactions caused by Rhizoma Paridis and its preparations, especially hepatotoxicity, has attracted significant attention in recent years; the Chinese Pharmacopoeia clearly describes its hypotoxicity and reminds the patient and doctor to note the possible problems of orally ingesting Rhizoma Paridis and its drug preparations in high doses or over prolonged periods and when taken with other liver-damaging drugs.

Experimental studies have shown that when the total saponin dose exceeds 4–5 times the recommended amount, significant liver damage occurs; in a zebrafish model, high doses of Rhizoma Paridis saponins caused scattered necrosis in liver tissue and disrupted hepatocyte arrangement.

Drug Delivery and Formulation Considerations

Intravesical instillation has been proposed as an administration route to avoid gastrointestinal toxicity and intravenous incompatibility. Despite the notable pharmacological activities of Paris species against multiple diseases, some mechanisms of action remain unclear; additionally, their extracts may cause adverse reactions and even toxicity, which to some extent restricts their widespread clinical application; there is an urgent need for further in-depth research on their chemical constituents, pharmacological effects, and toxic side effects, as well as the establishment of corresponding quality control standards and risk assessment systems.

Enduring Research Gaps

Future research and development of Rhizoma Paridis should not only focus on enhancing its antitumor activities and clarifying its antitumor mechanism, but also on reducing its toxicity and side effects; more clinical studies of the therapeutic safety of Rhizoma Paridis should be carried out to ensure the safety and efficacy of this TCM medicine and its active ingredients in anticancer therapy.

In summary, the current body of evidence for Paris polyphylla is substantial in terms of traditional use history and preclinical pharmacological characterization, but is limited by the near-total absence of controlled human clinical trials. The plant's safety profile requires careful attention to dose, duration of use, and concomitant hepatotoxic medications, as established in both classical TCM pharmacopoeial records and modern preclinical toxicological studies.

References

• Frontiers in Bioengineering and Biotechnology — Genetic Diversity, Chemical Components, and Property of Biomass Paris polyphylla var. yunnanensis (2021)
• Frontiers in Pharmacology — Paris spp (Liliaceae): A Review of its Botany, Ethnopharmacology, Phytochemistry, Pharmacological Activities, and Practical Applications (2025/2026)
• Journal of Ethnopharmacology (ScienceDirect) — The Traditional Uses, Phytochemistry, and Pharmacological Properties of Paris L. (Liliaceae): A Review (2021)
• Journal of Chemistry (Wiley) — Traditional Uses, Active Ingredients, and Biological Activities of Paris polyphylla Smith: A Comprehensive Review (2023)
• PMC — Bioactive Secondary Metabolites in Paris polyphylla Sm. and Their Biological Activities: A Review (Heliyon, 2022)
• PMC — Study of Chemical Compositions and Anticancer Effects of Paris polyphylla var. Chinensis Leaves (2022)
• Genetic Resources and Crop Evolution (Springer) — Paris polyphylla Sm.: A Threatened Herb of the Himalayas — Traditional Knowledge, Therapeutic Significance and Conservation Urgency (2025/2026)
• Plants (MDPI) — Ethnobotanical and Ethnopharmacological Study of Paris polyphylla var. yunnanensis in Yunnan Province, China (2024)
• PMC — Ethnobotanical and Ethnopharmacological Study of Paris polyphylla var. yunnanensis in Yunnan Province, China (2024)
• PMC / Frontiers in Pharmacology — Regulation of Anti-tumour Effects of Paris polyphylla Saponins via ROS: Molecular Mechanisms and Therapeutic Potentials (2025)
• PMC — Anticancer Effects of Paris Saponins by Apoptosis and PI3K/AKT Pathway in Gefitinib-Resistant Non-Small Cell Lung Cancer (2016)
• PubMed — Paris Saponin II Induced Apoptosis via Activation of Autophagy in Human Lung Cancer Cells (2016)
• PMC — Paris polyphylla Sm. Induces Reactive Oxygen Species and Caspase 3-Mediated Apoptosis in Colorectal Cancer Cells In Vitro and Potentiates the Therapeutic Significance of Fluorouracil and Cisplatin (2023)
• PMC — Polyphyllin VI Induces Apoptosis and Autophagy in Human Osteosarcoma Cells by Modulation of ROS/JNK Activation (2019)
• PubMed — Effects of Polyphyllin D, a Steroidal Saponin in Paris polyphylla, in Growth Inhibition of Human Breast Cancer Cells and in Xenograft (2005)
• PubMed — Polyphyllin VII Induces Apoptosis in HepG2 Cells through ROS-Mediated Mitochondrial Dysfunction and MAPK Pathways (2016)
• PMC / Frontiers in Pharmacology — Therapeutic Effects on Cancer of the Active Ingredients in Rhizoma Paridis (2023)
• PMC / Discover Oncology — Research Progress of Paris polyphylla in the Treatment of Digestive Tract Cancers (2024)
• PMC — Exploring the Toxicity Mechanisms and Detoxification Methods of Rhizoma Paridis (2025)
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• PubMed — Organ Toxicity of Paris polyphylla in Mice and the Underlying Hepatotoxic Mechanism Uncovered by an Integrated Network Toxicology and Transcriptomics (2026)
• PMC — Integrative Analysis of Proteomic and Metabonomics Data for Identification of Pathways Related to Rhizoma Paridis-Induced Hepatotoxicity (2020)
• PMC / Frontiers in Pharmacology — Lipidomics Indicates the Hepatotoxicity Effects of EtOAc Extract of Rhizoma Paridis (2022)
• ScienceDirect — Unveiling Polyphyllin's Role in Neuroprotection: A Pharmacological Perspective (2025)
• PMC — Mechanism Study of Cinnamomi Ramulus and Paris polyphylla Sm. Drug Pair in the Treatment of Adenomyosis by Network Pharmacology and Experimental Validation (2022)
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• PMC — Cytotoxic and Pro-apoptotic Effects of Botanical Drugs Derived from the Indigenous Cultivated Medicinal Plant Paris polyphylla var. yunnanensis (2023)
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• PMC / BMC Genomics — Endophyte-Inoculated Rhizomes of Paris polyphylla Improve Polyphyllin Biosynthesis and Yield: A Transcriptomic Analysis (2023)
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• IntechOpen — Paris polyphylla: An Important Endangered Medicinal Plants of Himalayan Foothills (2022)