Introduction

Plant-derived drug discovery has attracted considerable interest, and the development of phytopharmaceuticals pertains to an ethnopharmacological approach, which is a multidisciplinary field of inquiry exploring the anthropological perspectives and the pharmacological basis of medicinal plants. Various bioactive constituents present in a plant extract may exhibit the potential to modulate different proteins of certain signaling pathways, generating combined, preferred pharmacological effects. Moreover, the rapid development of herbal medicine, the publishing of papers focusing on complementary and alternative medicine, and the rising perception about how natural products alleviate diseases, particularly compared to conventional drugs with severe reported side effects, have added a stronger tendency to shift the pharmacotherapy paradigm to phytotherapy.

Of the megadiversity of medicinal plants, the Peperomia genus (Piperaceae), which comprises approximately 1,600 tropical species, has attracted many researchers to explore. Peperomia are annual or perennial herbs that grow on the surface of another plant (epiphytic), rocks (epilithic), or the soil (terrestrial). These herbs are often found in high and humid forests with plentiful rainfall. Many of the species show similar morphological characteristics; thus, their identification is challenging because the reproductive organs are tiny and easily fall off or are lost during harvesting. However, fewer than 50 species have been investigated for their chemical profiles, resulting in more than 200 isolated phytoconstituents.^1–5 Of those, gamma-sitosterol (C₂₉H₅₀O) was found in many Peperomia species, while linoelaidic acid (C₁₈H₃₂O₂), humulene (C₁₅H₂₄), and spathulenol (C₁₅H₂₄O) were mainly found in P. tetraphylla. Carotol (C₁₅H₂₆O) and apiole (C₁₂H₁₄O₄) were noticeably present in P. pellucida, and germacrene D (C₁₅H₂₄) was uniquely identified in P. dindygulensis.²

For initial study, we searched the PubMed database to find articles studying plants of the Peperomia genus, including those published between 1990 and 2025, resulting in 147 articles (summarized in Figure 1). PubMed is chosen for the resource of documents because this database supports the search and retrieval of biomedical, clinical, and life sciences references to improve health, both globally and personally, and covers more than 38 million citations and abstracts of biomedical and clinical literature. During the exploration we noted that a particular species namely Peperomia pellucida (depicted in Figure 2) was the most studied (49 articles), followed by, respectively, P. dindygulensis (15 articles), P. obtusifolia (11 articles), P. tetraphylla (9 articles), P. blanda (8 articles), P. galioides (6 articles), P. duclouxii (5 articles), while other species (in alphabetical order) such as P. alata, P. campylotropa, P. cavaleriei, P. circinata, P. cymbifolia, P. dolabriformis, P. emarginulata, P. fernandopoioana, P. fraseri, P. haematolepis, P. heptaphylla, P. heyneana, P. hispidula, P. inaequalifolia, P. incana, P. jamesoniana, P. kotana, P. laevifolia, P. leptostachya, P. macrostachya, P. masuthoniana, P. metallica, P. moulmeiniana, P. multisurcula, P. nakaharai, P. palmiformis, P. pilocarpa, P. pseudopereskiifolia, P. ranongensis, P. retusa, P. ricardofernandezii, P. riosaniensis, P. rotundata, P. rotundifolia, P. sagasteguii, P. scandens, P. serpens, P. sirindhorniana, P. symmankii, P. sui, P. trinervis, P. tuisana, P. vivipar, P. villipetiola, and P. vulcanica, were studied in only 1–2 articles. Most studies have described Brazil and China as locations where plant samples were collected.

Figure 1 Scattered diagram showing the number of articles on Peperomia genus plants (Piperaceae) published from 1990 to 2025 plotted against the year of publication.

Figure 2 The leaves and aerial parts of the Peperomia pellucida plant (this image was taken by the first author).

Considering that P. pellucida became the center of attention of many authors, this review limits the search period of publication to the last decade (2014 to 2025), thus ensuring the most updated studies of this plant. P. pellucida is a tropical herb, predominantly found in South America, Africa, Australia, and Southeast Asia (including Indonesia). In Indonesia, P. pellucida, with the local names sirih tumpang air (Indonesian) or suruhan (Javanese), and sasaladahan (Sundanese), is commonly used to alleviate pain and pyrexia. A handful of the whole plant is simmered with a half-liter of water and consumed daily until discomfort is resolved. To understand why this plant can suppress discomfort, we searched for relevant scientific information.

P. pellucida thrives in humid and shaded environments, and is distinguished by soft stems, trailing growth, and distinctive heart-shaped leaves with glossy and waxy surfaces. Numerous phytochemicals have been found in the leaves, stems, aerial parts, and roots of P. pellucida.^1–10 Therefore, this review aimed to identify the therapeutic potential, mechanisms of action, and toxicity studies of P. pellucida, assayed in cells and animal models, to provide a strong foundation for the clinical application of this plant in the future, bridging the gap between basic research and medical implementation. Furthermore, the ultimate goal is to offer recommendations for therapeutic development and to pave the way for clinical research to validate its therapeutic properties. Consequently, identifying the appropriate dosage and potential long-term side effects remains difficult, necessitating a comprehensive literature review to further explore the pharmacological activities of P. pellucida based on the existing preclinical evidence.

Methods

Relevant information regarding the pharmacological activities of P. pellucida was gathered through a search utilizing the PubMed and Scopus electronic databases. This search focused on studies that discussed the pharmacological activities of P. pellucida, including preclinical (in silico, in vitro, in vivo, cytotoxicity, and toxicity) and human studies, as well as its ethnopharmacological use.

The search on the PubMed database was filtered to 2014 to 2025 of the publication date, using the keywords “Peperomia pellucida AND pharmacology activity” resulted in 14 articles, “Peperomia pellucida AND molecular docking” resulted in 3 articles, “Peperomia pellucida AND in vitro” resulted in 8 articles, “Peperomia pellucida AND in vivo” resulted in 7 articles, and “Peperomia pellucida AND human studies” resulted in 7 articles. The collected articles were thoroughly screened based on their titles and abstracts by two authors. Duplicate articles, review articles, articles not written in English, articles not open-access, and articles not related to the topic were excluded. Another search in Scopus using the same keywords enriched the review.

Phytochemical Aspects

Phytochemical analysis of P. pellucida has identified various bioactive compounds, each of which plays a pivotal role in multifaceted therapeutic applications. Multiple parts of P. pellucida were reported for their metabolite content, such as diterpenoids eg, phytol (leaves and stems),^1,9 monoterpenoids and monoterpenes, e.g., linalool, D-limonene, and alpha-terpineol (stems),⁹ sesquiterpenes eg, beta-caryophyllene (leaves and stems),^2,9 sterols eg gamma-sitosterol (leaves and stems),² phenylpropanoids (leaves, stem, and roots),³ sesquiterpene hydrocarbons (leaves, stem, and roots),³ phenolics (aerial parts),⁴ flavonoids (leaves and stems),² glycosylated-flavonoids (leaves, stem, and roots),⁵ alkaloids (leaves, stem, and roots),⁵ benzodioxols and amides (leaves, stem, and roots),⁵ tannins (leaves),⁶ reducing sugars (leaves, stem, and roots),⁵ saponins (leaves, stem, and roots),^5,6 triterpenoids (leaves, stem, and roots),⁵ azulenes (leaves),⁷ carotenoids eg beta-carotene (leaves),⁷ secolignans (leaves, stem, and roots),⁸ tetrahydrofuran lignans (leaves, stem, and roots),⁸ methoxylated dihydronaphthalenone (leaves, stem, and roots),⁸ carbohydrates (leaves),⁶ water soluble vitamins (leaves),⁶ and minerals (leaves).⁶ Moreover, 17 evaporative esters, acids, and alcohol compounds were also found in the leaves of this plant.¹⁰

Pharmacology Activities

With the advancement of ethnopharmacological research, increasing evidence supports the potential of this plant as a promising candidate for medical therapies using in silico, in vitro, and in vivo assays. The most studied effects were antibacterial and anti-inflammatory, followed by antidiabetic, antihypertensive, anticancer, and antidepressant activities, and their effect on sperm count, viability, motility, and morphology. However, despite substantial pharmacological evidence, most studies have been limited to preclinical stages, and clinical data remain scarce. This poses a significant challenge for confirming the efficacy and safety of the plant for human use.

The leaves and aerial parts of P. pellucida were broadly explored and confirmed as the active components, followed by the stems, entire plants, and seeds. Table 1 (in silico study), Table 2 (radical scavenging activity), Table 3 (in vitro study), and Table 4 (in vivo study) summarize the pharmacological activities of P. pellucida published from 2014 to 2025.

Table 1 In silico Study of Bioactive Compounds Isolated from Peperomia Pellucida L. Kunth Reported in the Period from 2014 to 2025

Table 2 In vitro Radical Scavenging Capacity of Peperomia Pellucida L. Kunth. Reported in the Period from 2014 to 2025

Table 3 In vitro Pharmacological Activity and Cytotoxicity of Peperomia Pellucida L. Kunth. Reported in the Period from 2014 to 2025

Table 4 In vivo Pharmacological Activity and Toxicity of Peperomia Pellucida L. Kunth Reported in the Period from 2014 to 2025

In vitro Radical Scavenging Capacity

The radical scavenging capacity of P. pellucida has been verified using numerous reagents, such as 2,2- diphenyl-1-picrylhydrazyl (DPPH) radical,^{6,9,10,18–21} 2,2′-azino-bis (3- ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS),^9,18,21 ferrous reducing antioxidant capacity (FRAC),¹⁰ thiobarbituric acid assay (lipid peroxide radical),^9,18 inhibition of nitric oxide (NO) radical assay,⁹ hydrogen peroxide scavenging activity,¹⁸ reducing power (RP),²¹ and total antioxidant capacity.^18,21

The in vitro radical scavenging capacity of P. pellucida is summarized in Table 2, confirming a strong capacity of the leaves and the aerial parts of this plant in scavenging oxidant radicals. Although the location where the plants were collected was dissimilar, such as Nigeria,^6,9,18,20 Thailand,¹⁰ Malaysia,¹⁹ and Vietnam,²¹ and the polarity of the extraction solvent was diverse eg, methanol,^10,19 butanol,¹⁰ ethanol,⁹ ethyl acetate,¹⁰ and chloroform,⁶ the IC₅₀ obtained from various antioxidant assay techniques was reported to be similarly very low (ranging between 0.083 mg/mL and 2.83 mg/mL). This implies an intense radical scavenging capacity and confirms that antioxidants such as sterols, phenolic compounds, flavonoids, and carotenoids were present in an adequate amount in P. pellucida.

In silico Molecular Docking Study

In silico molecular docking study is broadly employed in pharmacology to predict the molecular interactions between drugs or drug candidates and their biological targets (proteins). There are limited PubMed-indexed articles reporting in silico studies of phytoconstituents contained in P. pellucida (tabulated in Table 1), among others, were phenylpropanoids,¹² lignans,^12,16 pheophorbide esters,¹³ polyphenols,¹⁴ ellagic acid,¹⁵ flavonoids,¹¹ and chromenes.¹⁷ The protein targets reported were those involved in estrogenic activities,¹² inflammation and pain,^13,16 hypertension,¹⁴ glucose metabolism,^15,17 and neuroprotection.¹¹

In one study, three phenylpropanoids and two lignan derivatives were molecular-docked to estrogen receptors (Erα with PDB ID: 1GWR and Erβ with PDB ID: 3OLS), and the binding energy resulting from the interaction was compared to that of 17β-estradiol. These phytoconstituents revealed similar capabilities to interact with both proteins, revealing their estrogenic activity.¹² Pellucidin A, a lignan compound, was reported by Queiroz et al (2020) for its strong binding to the active site of inducible NOS (iNOS) (PDB ID: 1M8D, endothelial NOS (eNOS) (PDB ID: 1M9J), and in the allosteric binding site of COX-2 (PDB ID: 4COX), which is similar to indomethacin, a known non-steroidal anti-inflammatory drug.¹⁶ The strong binding affinities of the P. pellucida phytoconstituents towards NF-κB p65 (PDB ID 9BDW) and PPAR-γ (PDB ID 3U9Q) have confirmed their anti-inflammatory activity. In this paper, Queiroz et al (2020) validated the in silico results with an in vitro study.¹³

A further search in the Scopus database using the same keywords (“Peperomia pellucida AND molecular docking”) and the publication period of 2014 to 2025 was performed, resulting in eight articles. Of those, three articles were excluded due to duplication with results in the PubMed database, and one article was published before 2014. The results are as follows:

Polyphenolic compounds from P. pellucida were molecular-docked towards angiotensin-converting enzyme (ACE) (PDB ID 1UZF) in complex with captopril, revealing the best binding affinity of tetrahydrofuran lignin with a value of −8.66 kcal/mol, which is better than captopril (−6.36 kcal/mol), thus revealing its potential as an antihypertensive agent.¹⁴ Dimethoxy ellagic acid obtained from the ethanol extract of the same plant interacted with aldose reductase (PDB ID 3S3G) and with alpha-amylase (PDB ID 1B2Y) and the DEA-enzyme complexes were stable for more than 100 ns, thus evidencing its role in modulating glucose metabolism.¹⁵ Similarly, peperochromene A obtained from P. pellucida has been shown to interact with four essential enzymes in carbohydrate metabolism, indicating its antidiabetic properties.¹⁷ The flavonoids acacetin, isovitexin, and apigenin of P. pellucida were molecular-docked towards human AChE (acetylcholinesterase) in complex with dihydrotanshinone I (PDB ID 4M0E), revealing that all the flavonoids interacted with the enzyme in similar binding mode with the standard drugs (donepezil; PubChem CID 3152 and rivastigmine; PubChem CID 77991), proclaiming their neuroprotective activity.¹¹

In vitro Pharmacological Activity Study

In silico studies need to be validated with in vitro and in vivo techniques, which have been reported in several papers. A search on the PubMed database using the keywords “Peperomia pellucida AND in vitro” resulted in eight articles;^{9,11,13,21–32} of those, two were excluded because they were not original articles. A further search in the Scopus database using the same keywords (“Peperomia pellucida AND in vitro”) and publication period of 2014 to 2025 was performed, resulting in 35 articles, of those, 26 articles were excluded either due to duplication with results in the PubMed database, articles were reviews/not original research, articles were short communications, articles were in silico or in vivo, articles were not related to the topic or only studying isolation technique of compounds, or articles did not discussing P. pellucida extract. The included articles portrayed assays of antibacterial,^9,22–28 anti-inflammatory,^13,29, neuroprotective,¹¹ repellent,³⁰ and antidiabetic activity,^21,32 as presented in Table 3.

Antibacterial, antifungal, and antiplasmodial activities of P. pellucida were reported in 8 articles in inhibiting Escherichia coli,^9,22,24,26 Enterobacter cloacae,⁹ Enterococcus faecalis,²³ Lactobacillus casei,²³ Listeria ivanovii,⁹ Mycobacterium smegmatis,⁹ Proteus mirabilis,²⁵ Pseudomonas aeruginosa,^22,24 P. fluorescens,²⁵ Staphylococcus aureus,^9,22,24,25 Streptococcus uberis,⁹ S. mutans,²³ S. mitis,²³ S. sanguinis,²³ S. salivarius,²³ S. sobrinus,²³ S. pneumoniae,²⁶ Salmonella typhi,²⁴ Bacillus subtilis,²⁵ Vibrio parahaemolyticus,⁹ Candida albicans,²⁸ and Plasmodium falciparum.²⁵

Anti-inflammatory activities were confirmed in human retinal pigment epithelial cell line (ARPE-19) exposed to high glucose and advanced glycation end product (AGE) under different glucose environments, as reported by Ho et al (2024). In this study, the methanol extract of P. pellucida collected in Selangor, Malaysia, and the ethyl acetate fraction significantly downregulated (p < 0.05) the expression of the pro-inflammatory and angiogenic markers, thus confirming their potential anti-inflammatory activity,¹³ and markedly suppressed the expression of IL-8 (p < 0.05), indicating its anti-inflammatory activity by altering the Janus kinase (JAK)-STAT3 pathway, as described by the same authors.²⁹

Inhibition of acetylcholine esterase (AChE) by P. pellucida plants was evidenced in two papers.^11,30 In the first study, the ethanol extract of P. pellucida plants collected from the Southwestern region of Thiruvananthapuram, Kerala, India, exhibited a weak neuroprotective activity by inhibiting AChE with an IC₅₀ value of 175.12 µg/mL.¹¹ This weak inhibition was consistent with the results of the authors’ in silico pharmacology study, revealing the molecular interaction of flavonoids contained in the plant with human AChE (PDB ID 4M0E).¹¹ The second article delineated that the hydrodistilled extract of the fresh leaves of this plant, collected from the Northern Caribbean Region, Colombia, could inhibit AChE, although weaker than chlorpyrifos, an organophosphate pesticide.³⁰

Other pharmacological activity assays of P. pellucida were reported by inhibiting the activity of alpha-amylase,²¹ alpha-glucosidase,^32, and xanthine oxidase,³¹ indicating the potential of this plant in alleviating various disorders.

In vivo Pharmacological Activity Study

Considering that studies of living organisms can be separated into in vitro (using parts of living organisms combined in tubes or plates) and in vivo (using animals), in conjunction with the rapid advancement of computational technologies (in silico),³⁹ a combination of the three approaches will provide comprehensive information. An in vivo study is usually conducted concerning the results derived from in vitro studies.

To better comprehend the in silico and in vitro studies of P. pellucida, a search of the PubMed database using the keywords “Peperomia pellucida AND in vivo” was performed, resulting in seven articles, of those, five articles were excluded because one article was not original research, one article studied hepatotoxicity (toxicity and cytotoxicity are discussed in different subsections), one article studied cytotoxicity and molecular docking, one article discussed the isolation of compounds with estrogenic activity, and one article was not related to the topic. A further search in the Scopus database using the same keywords (“Peperomia pellucida AND in vivo”) and publication period of 2014 to 2025 was performed, resulting in 21 articles, of which, 17 were excluded due to duplication with results in the PubMed database, articles were reviews/not original research, articles were in silico or in vitro although in their titles describing in vivo, articles were not related to the topic or only studying isolation technique of compounds, and articles did not discussing P. pellucida extract but synthetic compound.

The total of six articles included reported antihypertensive activity,⁴ antinociceptive,¹⁶ antiplasmodial,²⁷ anti-inflammatory,^35,36 and wound healing activity³⁷ of P. pellucida extracts, fraction, or metabolites (tabulated in Table 4).

Antihypertensive activity was explored by Saputri et al (2021), revealing that the ethyl acetate fraction of the aerial parts of P. pellucida collected at Bogor, West Java, Indonesia, decreased blood pressure and biomarkers associated with the renin–angiotensin–aldosterone systems (RAAS) in two-kidney, one-clip (2K1C) hypertensive model rats, comparable to that of captopril.⁴ The antihypertensive activity in hypertensive model rats is in line with the in silico results of polyphenols towards angiotensin-converting enzyme (ACE) reported by Ahmad et al (2019).¹⁴ Regrettably, we found no related in vitro study during the intended publication period.

Antinociceptive,¹⁶ anti-inflammatory,^35,36 and wound healing activity³⁷ of P. pellucida or its metabolite, pellucidin A, have been confirmed, which were in agreement with the results of the in silico study, describing the molecular interaction of P. pellucida metabolites with iNOS, eNOS, COX-2, NF-κB p65, and PPAR-γ,^13,16 and the in vitro study, delineating a significant downregulation of the pro-inflammatory cytokines, angiogenic markers, and altering the Janus kinase (JAK)-STAT3 pathway.^13,29

Cytotoxicity Study

It should be mandatory to guarantee the safety of a drug, whether it is a pure synthetic chemical or a plant-based drug; therefore, a search of the PubMed database using the keywords “Peperomia pellucida AND cytotoxicity” was carried out, resulting in three articles. Of these, one article was excluded because it was a review. A further search in the Scopus database using the same keywords (“Peperomia pellucida AND in vivo”) and the publication period of 2014 to 2025 was performed, resulting in eleven articles, of which only two were included. Articles were excluded due to duplication with results in the PubMed database, not related to cytotoxicity, published in 2011, and reviews/not original research.

The four papers included in this review reported that the extract of P. pellucida, collected from different sources, was confirmed to be non-toxic towards normal cells, namely, human retinal pigment epithelial cell line ARPE-19,¹³ and normal adult human dermal fibroblasts standard cell line,²² however, it inhibited the growth of cancerous cells, such as human breast adenocarcinoma (MCF-7),^33,34 and Vero cells.³³

Toxicity Study

Moreover, a search on the PubMed database using the keywords “Peperomia pellucida AND toxicity” resulted in nine articles; of these, only two articles were included because the others were either reviews or unrelated to a toxicity study, as follows:

Wild-type P. pellucida collected from Can Tho City, Vietnam, was extracted using 96% ethanol and subjected to acute and subchronic toxicity assays in mice. The extract at a dose of 5000 mg/kg body weight resulted in no acute toxicity in mice after seven days of consumption, as evidenced by the absence of mortality or abnormalities, such as convulsions, ruffled hair, diarrhea, or vomiting. The 28-day subchronic toxicity observation revealed that a dose of 500 mg/kg body weight did not cause any adverse reactions or clinical signs of toxicity. Hematological parameters, including MCV (mean corpuscular volume), HGB (hemoglobin), HCT (hematocrit), MCH (mean corpuscular hemoglobin), and MCHC (mean corpuscular hemoglobin concentration), remained unaltered when exposed to the extract.¹⁰

The aerial parts of P. pellucida obtained from Claveria, Misamis Oriental, Philippines, extracted with water (decoction and freeze-dried extracts), were tested for subchronic toxicity in BALB/c mice for 9 weeks. This study revealed that the 60 mg/kg body weight of freeze-dried extract contributed to a decrease in appetite. Long-term administration of the extracts did not alter the levels of serum alanine aminotransferase (ALT) (the liver enzyme), thus confirming their safety to the liver. However, the extracts were mutagenic at high concentrations.³⁸

Ethnopharmacological/Ethnobotanical Survey

Although many studies have reported the in silico, in vitro, and in vivo approach of P. pellucida, in the form of extracts, fractions, or metabolites, it is regrettable that no human studies were recorded in the PubMed database in the publication period of 2014 to 2025, while the search in the Scopus database for open-access articles, after thorough screening by title and abstract, resulted in seven ethnopharmacological/ethnobotanical studies,^40–46 which described the use of P. pellucida for general health purpose,⁴⁰ to treat respiratory disorders,⁴⁰ to cure cancer,⁴⁰ hepatoprotector,⁴¹ to treat numerous infections,^43,44 and other diseases. These ethnopharmacological surveys are closely related to the in silico, in vitro, and in vivo pharmacological assays of P. pellucida in the last decade. Polyphenols, flavonoids, lignans, and sterols contained in the aerial parts of this plant are considered to contribute greatly to the pharmacological activities. The detailed descriptions of the ethnopharmacological surveys are as follows:

In the first article published in 2014, information on demographic data and plant use methods was recorded through direct interviews with 200 participants. The study protocol was approved by the National University of Singapore Institutional Review Board, and informed consent was obtained from all the participants. This study documented 414 medicinal plants, grown in Singapore and used by the participants from 2009 to 2014, including P. pellucida. The herbs were mostly consumed in dried form for general health purposes or to treat respiratory-related disorders, although some were purchased as products. Indigenous knowledge was verbally transferred from older generations residing in many kampong villages in Singapore.⁴⁰ The second article, published in 2020, describes the use of medicinal plants to treat jaundice by the tribes of the Morigaon District, Assam, India. The survey was conducted from June 2016 to July 2017. Data were collected using a semi-structured questionnaire and evaluated using quantitative ethno-botanical indices: fidelity level (FL), use value (UV), and family use value (FUV). This study portrayed 27 plant families, with the highest use being Lamiaceae, Leguminosae, Acanthaceae, Oxalidaceae, Phyllanthaceae, Piperaceae, Poaceae, and Rutaceae. Among these, P. pellucida (Piperaceae) has been documented and noticed for its hepatoprotective activity.⁴¹ A quantitative ethnobotanical study of medicinal plants in Ile-Ife, Osun State, Nigeria, was conducted through semi-structured interviews with 70 participants. Data were analyzed using the ethnobotanical knowledge index (EKI), species popularity index (SPI), relative frequency of citation (RFC), cultural importance index (CII), informant consensus factor (FIC), FL, and species therapeutic index (STI). This study identified 87 plant species belonging to 43 families, with the Euphorbiaceae family and leaves being the most used. Some of the recorded medicinal plants include Rauvolfia vomitoria, Senna alata, Crinum jagus, Kigelia africana, P. pellucida, Solanum verbascifolium, Cnestis ferruginea, Ageratum conyzoides, and Jatropha multifida.⁴² An ethnobotanical survey and interview were conducted in ten villages in Myanmar in 2018. Data were collected from interviews with 131 participants, recruited using the snowball sampling method. The therapeutic applications of the plants were categorized according to the ICPC-2 standard. Voucher plant specimens were collected and identified by experts. The data were evaluated by applying the use report (UR) per species in the EthnobotanyR (https://cran.r-project.org/web/packages/ethnobotanyR/vignettes/ethnobotanyr_vignette.html). A total of 158 species belonging to 64 families, including P. pellucida, were used in Myanmar. The participants listed 78 therapeutic uses of these plants, which were classified into 16 ICPC-2 disease categories. Digestive, urological, and respiratory diseases ranked first. Fabaceae was the most represented family. The leaves were the most commonly used plant part, while boiling and oral administration were the most preferred consumption techniques.⁴³ Another ethnopharmacological study of the medicinal plants in the central part and the Northern district of Bangladesh has been carried out, involving 127 face-to-face participants, including Ayurvedic practitioners, patients, and local people. Data were analyzed using quantitative indices including UV, informant consensus factor (ICF), FL, and rank order priority (ROP). The survey documented 71 species of 44 families, including P. pellucida, which have been used to treat numerous infections. The most cited plant families were, in respective order, Lamiaceae, Meliaceae, and Leguminosae. Leaves were the most frequently used plant part in preparation. Pneumonia bacteria were recorded for their highest FIC value.⁴⁴ Plants contribute an essential role in the indigenous medicine of the Nias tribe in North Sumatra, Indonesia. Knowledge was transferred from the older generation to the younger generation; thus, this ethnopharmacological survey was carried out through questionnaires, interviews, and observations to collect and document the knowledge. Participants were recruited using the snowball sampling method. Taxonomical identification was carried out at the Medanense Herbarium. Quantitative analysis was performed by calculating the frequency of quotations (FOQ), the ratio of informant agreement, and the citation frequency (CF). The survey resulted in 50 plant species of 26 families being used by the people of Nias, among which was P. pellucida, local name tima-tima, with a CF value of 56.49%.⁴⁵ Furthermore, an ethnobotanical study of plants used by local people in the upper region of Bengawan Solo River, Central Java, Indonesia, was performed using qualitative and quantitative data obtained by conducting open, semi-structured, and structured interviews with 90 adult participants. Quantitative data was analyzed to produce UV and informant consensus factor (ICF). This study concluded that the community used 49 species of 32 families, and the most consumed were Leucaena leucocephala, Carica papaya, Dendrocalamus asper, Muntingia calabura, P. pellucida, Gnetum gnemon, Moringa oleifera, and Portulaca oleracea, with an ICF value ranging from 0.645 to 1.⁴⁶

Despite the lack of recent studies on P. pellucida in humans, in an article published in 1999, a 20% decoction of P. pellucida at a dose of 2 mL/kg body weight given orally was described to reduce the intraocular pressure (IOP) by 18% within 4 h in 40 glaucoma patients.⁴⁷

Moreover, as a promising plant-derived drug, P. pellucida in spray-dried powder form (spray-dried at atomization temperatures of 140, 160, and 180°C), developed using the diluent Flowlac, was reported to meet physicochemical quality control parameters, thus confirming its readiness for technological development for pharmaceutical applications.⁴⁸

Discussion on the Mechanism of Action of Bioactive Compounds

The multifaceted impact of bioactive compounds on different signaling proteins in the body suggests a complex network of interactions. P. pellucida is known for its numerous phytochemical contents or bioactive compounds; therefore, the mechanism of action of the main constituents is considered noteworthy.

Diterpenoids such as phytol have been reported to be present in the leaves and stems of P. pellucida.^1,9 In a review by Islam et al, phytol as a single compound was shown to activate apoptosis and autophagy in human gastric adenocarcinoma AGS cells, and downregulate protein kinase B (Akt), mTOR (mechanistic target of rapamycin), and p70S6K phosphorylation. Phytol exhibits anxiolytic, metabolism-modulating, cytotoxic, antioxidant, antinociceptive, anti-inflammatory, immune-modulating, and antimicrobial activities.⁴⁹ Other researchers, Ko and Cho (2018), delineated that phytol suppressed the expression of microphthalmia-associated transcription factor (MITF) by phosphorylating extracellular signal-regulated protein kinase (ERK) in B16F10 cells, thus suggesting its potential as a therapy for skin hyperpigmentation.⁵⁰ Moreover, phytol is also involved in the NF-κB signaling pathway, hence reducing the pro-inflammatory cytokines TNF-α and IL-6.⁵¹

Monoterpenoids and monoterpenes such as linalool, D-limonene, and alpha-terpineol are present in the stems, while sesquiterpenes, such as beta-caryophyllene, are found in the leaves and stems of P. pellucida.^2,9

Linalool (a monoterpene acyclic tertiary alcohol), as a single compound, has been studied for its antibacterial activity and mechanism of action against P. fluorescens. This monoterpene reduces the bacteria’s membrane potential, changes the alkaline phosphatase levels, and releases DNA, RNA, and protein of the cell wall membrane structure, and disrupts the cytoplasmic contents.⁵² Linalool increases the levels of histidine and methionine, which are involved in the structural phenotype of the bacterial biofilm.^53,54 Moreover, linalool exhibits antidepressant effects by targeting numerous systems in the body, such as in the monoaminergic transmission, where it interacts with the serotonergic and noradrenergic pathways. In the hypothalamus-pituitary-adrenal axis, linalool modulates the expression of stress-related genes, elevates oxytocin and neuropeptide Y levels, and reduces salivary cortisol.⁵⁵ In a study on the triple transgenic model of Alzheimer’s disease mice, linalool showed improvement in learning, spatial memory, and behavior of the mice. Linalool significantly reduced extracellular beta-amyloidosis, tauopathy, astrogliosis, and microgliosis in the hippocampus and amygdala of mice, and suppressed the levels of p38 MAPK, NOS2, COX-2, and IL-1β.⁵⁶

Limonene (1-methyl-4-isopropenylcyclohex-1-ene) is a natural monocyclic monoterpene, which has been reported for its antibacterial and anti-inflammatory activities.⁵⁷ D-Limonene increased the permeability of the cell membrane, altered membrane potential, and reduced heat resistance, thus leading to the leakage of intracellular substances and cell lysis.^58,59 In preclinical studies, d-limonene exhibited anti-inflammatory activity by suppressing the production of TNF-α, IL-6, IL-1β, and NF-κB, and elevating the level of IL-10 and glutathione peroxidase (GPX), thus maintaining the integrity of the inflammation site.⁶⁰ Furthermore, the anti-inflammatory activity of D-limonene in COVID-19 pulmonary fibrosis was confirmed that this compound could block the PI3K/Akt/IKK-α/NF-κB p65 signaling pathway.⁶¹

Alpha-terpineol inhibited the activity and translocation of NF-κB to the nucleus, thus restricting the transcription of NF-κB-related pro-inflammatory gene expression.⁶² In another study, alpha-terpineol inhibited the activity of bovine COX-1 and COX-2 with an IC₅₀ value of 5.14 mM and 0.69 mM, respectively.⁶³

Beta-caryophyllene induces apoptosis via ROS-mediated MAPKs and inhibition of the AKT/PI3K /mTOR/S6K1 pathways. It also inhibits invasion and induces apoptosis via suppression of the NF-κB pathway. The anti-inflammatory activity was achieved via downregulation of TLR-4, IL-1ß, and TNF-α levels.⁶⁴ It was also reported for its neuroprotective activity in a review article.⁶⁵

Other bioactive compounds, such as gamma-sitosterol, were found in the leaves and stems,² phenolics in the aerial parts,⁴ and flavonoids in the leaves and stems.² Gamma-sitosterol was cytotoxic against Caco-2, HepG2, and MCF-7 with IC₅₀-values of 8.3, 21.8, and 28.8 μg/mL, respectively,⁶⁶ and in another study, it inhibited the cell proliferation by 42.18 ± 3.9% for MCF-7 and 44.36 ± 3.05% for A549 cells.⁶⁷ Phenolics were widely recognized for their strong radical scavenging capacity. In accordance with the Trolox equivalent antioxidant capacity (TEAC), FRAP, and hypochlorite scavenging activity, the order was procyanidin dimer > flavanol > flavonol > hydroxycinnamic acids > simple phenolic acids. Quercetin exhibited stronger radical scavenging capacity compared with myricetin and kaempferol. Moreover, among simple phenolics and hydroxycinnamic acids, gallic acid and rosmarinic acid are the strongest radical scavengers, respectively.⁶⁸

Conclusion

Our study of the articles published between 2014 and 2025 confirms that P. pellucida is still being explored globally. The most explored parts of the P. pellucida plant in numerous in vitro and in vivo studies are the leaves and the aerial parts, which are considered the active parts. Methanol and ethanol are the commonly employed solvents for extraction, and the extraction at room temperature is the popular choice. Considering the notable findings of the in silico, in vitro, and in vivo studies, P. pellucida may have the potential to be further developed as a plant-based antimicrobial, anti-inflammatory, antihypertension, or hypoglycemic agent. These activities are supported by their bioactive compounds, in particular, polyphenols, flavonoids, lignans, and sterols. Moreover, this plant did not show toxicity towards numerous normal cells or animal models, but was reported to be toxic towards cancer cells, such as MCF-7 and Vero cells, implying the potential as anticancer. During the study period, we did not find studies in humans, however, several articles describing ethnopharmacological surveys of medicinal plants in Singapore, India, Myanmar, Nigeria, and Indonesia were found, among which P. pellucida was mentioned, to treat respiratory disorders, to cure cancer, to treat numerous infections, and for general health purpose, thus agree with the results of pharmacological activity assays. Despite its promising pharmacological evidence, the clinical applications of P. pellucida remain limited due to a lack of human studies, presenting challenges in determining its safety, dosage, and long-term effects. Further research for clinical validation is essential to determine its potential as a therapeutic agent.