1. INTRODUCTION:

Ficus religiosa L. (F. religiosa) also known as the Sacred Fig, Bo Tree, or Peepal Treeis a member of the Moraceae family and is highly significant in South Asian Countries, where it is revered as the “Bodhi Tree” under which Siddhartha Gautama, later known as Buddha, attained enlightenment and has a wealthof medicinal, ecological, cultural, and religious significance.¹F. religiosa is native to the Indian subcontinent but has been introduced to various tropical-subtropicalregions around the world. It is commonly found in countries across Asia, including Pakistan, China, Nepal, Sri Lanka, Bangladesh, and Southeast Asian Nations.² This tree plays a vital role in supporting biodiversity by providing habitat and food for various species of birds and insects. F. religiosa contributes to soil conservation and fertility also. Its dense foliage providesshade, helping to maintain a suitable microclimate in its surroundings.³

Ethnomedicinal practices of F. religiosa have been deeply rooted in traditional medicine systems. Indigenous communities utilized different parts of this plant for treating a wide array of ailments.

The leaves, bark, roots, fruits (figs), and latex have been employed in traditional remedies to address conditions ranging from gastrointestinal disorders to skin ailments and even chronic diseases like cancer, heart-related disease, etc. showing the plant’s versatile therapeutic potential. Phytochemical analysis has identified a plethora of secondary metabolites, like flavonoids, alkaloids, terpenoids, phenolics, and glycosides from various parts of the plant. These bioactive compounds contribute to the plant’s pharmacological activities and are associated with diverse health benefits. Understanding the chemical composition of F. religiosa is key for elucidating its therapeutic mechanisms and potential applications in modern medicine. Many studies have elucidated the plant’s antioxidant, antimicrobial, antitumor, anti-inflammatory, antidiabetic, hepatoprotective, antiallergic, analgesic, and antipyretic activities.

These findings not only validate the efficacy of F. religiosa in traditional medicine but also lay the way for contemporary healthcare practices.

The multifaceted nature of F. religiosa in both traditional and modern medicine requires a comprehensive and systematic review of the existing knowledge and highlighting potential avenues for future research. This review will provide valuable insights into the ethnomedicinal practices associated with F. religiosa, the bioactive constituents responsible for its pharmacological effects, and describe its therapeutic potential in various diseases.

2. METHODOLOGY:

The methodology for writing a comprehensive and systematic review of F. religiosa involves rigorous literature search strategies, data extraction, and critical analysis to provide a thorough overview of its ethnobotanical uses, bioactive constituents, and pharmacological applications. The first step in conducting this review involves defining clear research objectives and establishing inclusion and exclusion criteria. Next, an extensive literature search is conducted through various electronic databases, including PubMed, Web of Science, Google Scholar, Science Direct, Wiley Online Library, Research Gate, Scopus, and MDPI. Keyword combinations such as Ficus religiosa, Peepal, Ethnobotany, Phytochemistry,and Pharmacologyare utilized to review relevant documents. Information related to ethnobotanical uses, bioactive constituents, and pharmacological properties of F. religiosa is systematically collected and recorded. Data extraction isconducted independently by multiple reviewers to minimize bias and errors. After extracting the data,focus is placed on providing a comprehensive overview of the current state of knowledge regarding F. religiosa and its potential applications in healthcare and medicine. Finally, the findings of the review are presented in a structured format within the manuscript.

3. BOTANICAL DESCRIPTION:

The sacred fig isadeciduous, medium to large-sized tree that can reach heights of up to 30 meters.⁴Itpossesses a straight, cylindrical bole with a grayish bark that tends to flake off in patches. The young branches are often covered with a thin, smooth, and pale bark.⁵ The leaves of F. religiosa are distinctive and have a cordate or heart-shaped base, with a pointed apex.² The leaves are characterized by a long petiole and prominent drip tips. The leaf margins are often serrated, and the surface is glabrous. The arrangement of leaves is alternate along the branches (Figure 1).⁶

Figure 1. F. religiosa,A:Tree, B: Stem, C: Leaves, D:Fruits/Figs (Immature)

Thereproductive structures are very unique, the flowers of this species are small and inconspicuous, arranged within a structure called a syconium, which is a specialized hollow receptacle. The syconium resembles a small, roundfruit and is the main reproductive organ of the tree. Once mature, the syconium becomes a fig-like fruit, and the seeds are dispersed through the droppings of birds and other animals that consume the fruit.⁷

4. Taxonomic Classification and Vernacular Names

Domain	Eukarya
Kingdom	Plantae
Subkingdom	Tracheophyta
Superdivision	Spermatophyta
Division	Magnoliophyta
Class	Magnoliopsida
Subclass	Rosidae
Order	Rosales
Family	Moraceae
Genus	Ficus
Species	F. religiosaL.
Vernacular Names	Hindi: Peepal, Pipla, Ashvattha, Bodhi-Vrksha English: Sacred Fig, Bo Tree, Peepul Tree Assamese: Ahant Bengali: Ashud Gujarati: Piplo, Piparo, Pipalo, Jari Kannada: Bodhi Mara Marathi: Pedhe Oriya: Pipala Punjabi: Bargadh Tamil: Arasu, Arayam Telugu: Pedda Jandhi

Sources: 1,2,8,9

5. ETHNOMEDICINALUSES:

F. religiosahas a wide range of uses in traditional medicine systems across different cultures and communities.⁴Various parts of the tree (leaves, bark,roots, etc.) are utilized for their medicinal properties (Table 1). The leaves, in particular, are rich in compounds such as tannins, flavonoids, and alkaloids, contributing to their therapeutic potential. Oneof the prominent uses of F. religiosa in traditional medicine is its role in treating gastrointestinal disorders. The leaves possess laxative properties, aiding in digestion and relieving constipation.¹⁰Additionally, the bark is often used to prepare decoctions that have antidiabetic and renoprotective properties.¹¹This tree’s extracts are also utilized in the treatment of respiratory ailments, including asthma and bronchitis.¹² The anti-inflammatory and antimicrobial properties of F. religiosa make it a valuable resource in combating various infections and inflammatory conditions.¹³The latex obtained from the bark of this plant which is commonly known as “Peepal Sap”is applied topically to treat wounds and skin disorders. The latex contains compounds with antimicrobial properties, facilitating the healing process.¹⁴Thesap is also used traditionally for dental health, which strengthens teeth and gums.¹⁵

6. Nutritional Value And Their Health Benefits:

The F. religiosa has been also used as a food source in various traditional practices due to its nutritional value which has various health benefits. The leaves of F. religiosaare a rich source of essential nutrients such as vitamins, minerals, proteins, and carbohydrates. Studies have shown that the leaves containa good amount of vitamins (A, C, and K) as well as minerals like calcium, iron, and potassium. These nutrients play crucial roles in maintaining overall health and well-being.²⁵ Also, the fruits (Figs) of F. religiosa are known to be a good source of dietary fiber, which aids in digestion and promotes gastrointestinal health (Table 2).²⁶They also contain antioxidants such as flavonoids and polyphenols, which help to neutralize harmful free radicals and reduce oxidative stress. This reduces the risk of chronic diseases like cardiovascular diseases, cancer, and neurodegenerative disorders.²⁷The presence of calcium and vitamin K in F. religiosa leaves supports bone health and helps in preventing conditions like osteoporosis.²⁸Also, Vitamins A and C found in F. religiosa leaves play a vital role in supporting the immune system, thus helping the body fight against infections and diseases.²⁹The dietary fiber present in F. religiosa fruits aids in digestion prevents constipation and promotes gut health. Italso helps in reducing the risk of gastrointestinal disorders such as irritable bowel syndrome.^30,31

Table 2. Nutritional constituents of F. religiosafruit (fresh and dry) per 100 g

Nutrients		Fresh Fruit	Dried Fruit
Macronutrients	Moisture	62.4g	18.8g
	Carbohydrates	21.2g	68.33g
	Protein	2.5g	8.48g
	Fat	1.7g	0.14g
	Dietary Fiber	9.9g	2.97g
Micronutrients	Calcium	289mg	848mg
	Iron	1.4mg	6mg
	Phosphorus	83mg	-
	Magnesium	49mg	-
	Potassium	209mg	-
	Vitamin A	15.41mg	20.1mg
	Vitamin C	30mg	21.6mg

Sources:32-34

6. BIOACTIVE CONSTITUENTS:

F. religiosa has been a subject of scientific interest for a long time ago due to its rich availability of bioactive constituents.³⁴ The bioactive compounds present in F. religiosa contribute to its medicinal properties and therapeutic potential.It is a treasureof bioactive compounds, encompassing a wide range of phytochemicals such as alkaloids, flavonoids, tannins, glycosides, steroids, and essential oils.^35,36These compounds are distributed throughout various parts of the tree, including fruits, leaves, bark, roots, etc., each having its own unique set ofbioactive constituents.³⁷The following headings discuss them in detail:

6.1. Alkaloids:

Alkaloids are nitrogen-containing organic compounds known for their diverse physiological effects. F. religiosa has been found to contain alkaloids like Ficus-amine, isoleucine, and isoprenaline in the bark (Figure 2). These alkaloids exhibit various biological activities, including anti-cardiovascular, analgesic properties, and anti-inflammatory.³⁸

6.2. Flavonoids:

Flavonoids, a class of polyphenolic compounds, are abundant in F. religiosa leaves. Quercetin, kaempferol, and rutin are some of the major flavonoids identified (Figure 2). These compounds possess antioxidant properties, scavenging free radicals and preventing oxidative stress. Additionally, they exhibit anti-inflammatory and anti-cancer activities.³⁹

6.3. Tannins:

Tannins are also polyphenolic compounds that contribute to the astringent taste of plants. F. religiosa bark is rich in tannins, like punicalin and punicalagin (Figure 2). Tannins possess antimicrobial properties and are known for their ability to inhibit the growth offungi andbacteria.⁴⁰

6.4. Glycosides:

Glycosides are compounds containing a sugar molecule bonded to a non-sugar moiety. F. religiosa contains glycosidessuch as p-coumaroyl glycoside and bergenin in leaves and bark respectively (Figure 2). Bergenin has been studied for its anti-inflammatory and hepatoprotective effects.^41,42

6.5. Steroids:

Steroids are another class of bioactive compounds present in F. religiosa. β-sitosterol, a common plant steroid, has been identified in the leaves and bark of the sacred fig (Figure 2). β-sitosterol exhibits anti-inflammatory and cholesterol-lowering properties.^43,44

6.6. Essential Oils:

The essential oils extracted from various parts of F. religiosa contribute to its aromatic properties. These oils contain volatile compounds such as eugenol, linalool, and camphor (Figure 2). They are known for their antimicrobial, antidiabetic, anticancer, and analgesic properties.^45-47

Figure 2. Chemical structures of important bioactive compounds identified from various parts ofF. religiosa

7. PHARMACOLOGICAL PROPERTIES:

7.1. Antioxidant Activity:

Several studies identified specific compounds like gallic acid, quercetin, rutin, and myricetin as significant contributors to antioxidant activity.⁴⁸Research indicates that different parts of this plant possess varying degrees of antioxidants, suggesting that leaves, bark, and stem buds exhibit significant free-radical scavenging activity.⁴⁹However, extraction methods significantly impact the yield and potency of antioxidant compounds.⁵⁰ Recent studies reported that polar solvents like methanol and ethanol are the most potent fractions for extracting. Through free radical scavenging (DPPH and ABTS), these extracts exhibit the abilityto neutralize harmful entities thus safeguarding against cellular damage.⁵¹Furthermore, these extracts showcase potential in inhibiting enzymes responsible for free radical production, notably xanthine oxidase and myeloperoxidase.⁵²Such antioxidant properties of F. religiosa revealed its therapeutic potential, particularly in neurodegenerative diseases like Parkinson’s and Alzheimer’s, where oxidative stress plays a pivotal role. Moreover, the antioxidant activity of F. religiosa offers protection against cellular damage associated with chronic diseases like diabetes and cardiovascular disorders.⁵³Overall, the various antioxidant mechanisms of F. religiosa underscore its potential as a therapeutic agent in combating various diseases characterized by oxidative stress.

7.2. Antimicrobial Activity:

Astudy reported that leaf extracts inhibited the growth of Staphylococcus aureus and Escherichia coli at concentrations as low as 25mg/ml.⁵⁴ Similarly, bark extracts displayed anti-fungal properties against Aspergillus niger and Candida albicans at concentrations between 50-100mg/ml.⁴⁹Interestingly, studies have also found F. religiosa extracts are effective against multidrug-resistant bacteria, offering hope in the fight against antibiotic resistance.⁵⁵Beyond antibacterial and antifungal properties, F. religiosa extracts have also shown promise against parasites and viruses. Another study demonstrated the larvicidal potential of leaf extracts against Aedes aegypti, the mosquito vector of dengue fever.⁵⁴Additionally, research suggests antiviral activity against herpes simplex virus and influenza A virus, highlighting the multifaceted nature of this plant’s antimicrobial potential.⁵⁶

7.3. Antitumor Activity:

The aqueous extracts of F. religiosa leaves have emerged as powerful allies against cancer. A study demonstrated significant cytotoxicity against breast cancer cell lines (MCF-7) at concentrations ranging from10-20mM. The mechanism of action involved the upregulation of tumor suppressor genes p53, p21, and pRb, leading to cell cycle arrest and apoptosis.⁵⁷These findings suggest the leaves hold promise for future therapeutic development. Also, the bark of F. religiosa has potent antitumor activity. A study revealed the ethanol extract’s antiproliferative effect against HeLa cervical cancer cells with an IC₅₀ value of 18.75μg/ml. Further, the extract induced apoptosis and cell cycle arrest, highlighting its potential as a therapeutic candidate.⁵⁸These findings underscore the bark’s potential as a source of novel antitumor agents.

7.4. Anti-inflammatory Activity:

Various studies highlight the anti-inflammatory potential ofleaves from this tree. An aqueous leaf extract demonstrated promising results in reducing inflammation in carrageenan-induced paw edema in rats at a dose of 250mg/kg body weight, comparable to the effects of standard drugs like indomethacin and aspirin.⁵⁹Also, the bark of F. religiosa exhibits anti-inflammatory activity. An aqueous bark extract effectively reduced paw edema in carrageenan-induced inflammation at a dose of 200mg/kg body weight, showcasing comparable efficacy to diclofenac.⁶⁰Furthermore, astudy using fruit extract observed its ability to inhibit the production of inflammatory mediators like nitric oxide and pro-inflammatory cytokines. While dosage information for fruits remains limited, further research could unlock their potential.⁶¹

7.5. Antidiabetic Activity:

Various studies have revealed that leaf extracts possess hypoglycemic properties, contributing to glucose regulation. Dosage limits in these studies have varied, with effective doses typically ranging from 100-500 mg/kg body weight in experimental animal models. These doses have demonstrated significant reductions in blood glucose levels, indicating the potential of F. religiosa leaf extracts as a complementary approach to diabetes management.⁶²Also, the bark extracts have shown promising results in improving glycemic control, with dosages ranging from 200-600mg/kg body weight in animal studies. These doses have exhibited notable reductions in fasting blood glucose levels and glycosylated hemoglobin, highlighting the therapeutic significance of F. religiosabark in diabetes management.⁶³Furthermore, fruit extracts have demonstrated hypoglycemic activity, with effective doses varying between 150-400mg/kg body weight in preclinical studies. These doses have shown considerable improvements in insulin sensitivity and pancreatic β-cell function, indicating the potential of F. religiosafruits asan alternative therapy for diabetes mellitus.^37,64

7.6. Hepatoprotective Activity:

Research demonstrated the hepatoprotective effects of F. religiosa leaf extracts in an animal model of liver injury induced by hepatotoxic agents. The study reported a significant reduction in markers of liver damage, such as serum ALT(alanine aminotransferase) and AST(aspartateaminotransferase), with administration of leaf extracts at a dosage of 200mg/kg body weight.⁶⁵Investigations revealed the hepatoprotective potential of F. religiosa latex and bark extracts against chemically induced liver damage in rats. The study observed a dose-dependent reduction of liver injury markers and oxidative stress parameters with the administration of latex and bark extracts at doses ranging from 150-500 mg/kg body weight.⁶⁶A recent research explored the hepatoprotective activity of F. religiosa fruit extracts in a murine model of hepatic injury induced by toxins. The study highlighted a dose-dependent improvement in liver function tests and histopathological changes with the administration of fruit extracts, with an effective dosage range of 150-300mg/kg body weight.⁶⁷Another study investigated the hepatoprotective effects of F. religiosa root extracts in an experimental model of liver toxicity induced by xenobiotics. The findings demonstrated significant amelioration of liver damage markers and enhancement of antioxidant defenses with root extract administration at doses of 250-500mg/kg body weight.⁶⁸

7.7. Analgesic and Antipyretic Activities:

According toa study, the analgesic activity of F. religiosaleaf extract in animal modelsdemonstrated significant pain-relieving effects, with dosage limits ranging from 200-800mg/kg body weight, with optimal analgesic effects observed at higher doses.⁶⁹Similarly, another recent study investigated the antipyretic activity of F. religiosa bark extract. The findings revealed promising antipyretic effects, with dosage limits ranging from 300-1200mg/kg body weight in a dose-dependent manner.⁷⁰

7.8. Antiallergic Activity:

A study highlighted the anti-allergic properties of F. religiosaleaf extract. The dosage limit recommended in this study was 200-400mg/kg body weight.⁷¹ Additionally, a review discussed the anti-allergic activity of F. religiosabark extract.The recommended dosage ranged from 300-500mg/kg body weight,as suggested by experimental research carried out on animal subjects.⁷²

8. SAFETY AND TOXICITY:

Several studies have investigated the toxicity of F. religiosa extracts to define safe dosage limits and potential adverse effects.Studies assessing the acute and chronic toxicity of F. religiosa extracts in animal models have reported varying outcomes.In acute toxicity studies, the administration of high doses of F. religiosa extracts did not obtain significant adverse effects in experimental animals. For instance, a study observed no signs of toxicity or mortality in rats following oral administration of F. religiosa extract at doses up to 2000 mg/kg body weight.⁷³ Similarly, a chronic toxicity study demonstrated the absence of organ toxicity or histopathological alterations in rats treated with F. religiosa leaves extract.⁷⁴Several researchers have proposed dosage recommendations for F. religiosa extracts based on their pharmacological effects and toxicity profiles, which most of the time between 100-500mg/kg according to the body weight of the animal model. Lastly, all the safety margins of F. religiosa extracts may vary depending on factors such as extraction methods, solvent used, and plant parts employed. Excessive consumption of F. religiosa extracts may lead to potential adverse effects like gastrointestinal disturbances, allergic reactions, or hepatotoxicity. Thus, it is very important to establish safe dosage limits through rigorous preclinical and clinical studies.

9. Future Challenges and Research Directions:

The key notable challenge is the need for more comprehensive and systematic phytochemical profiling to identify and isolate novel bioactive compounds present in various parts of F. religiosa.While existing studies have only highlighted the constituents such as flavonoids, phenolic compounds, alkaloids, and terpenoids majorly, but there aremany more to uncover with promising pharmacological peripeties. Advanced analytical techniques must be integrated with bioassays that can facilitate the isolation and characterization of these compounds that help in the development of new drugs or therapeutic agents. Investigations through in-vitro and in-vivo techniquescan elucidate the mechanisms underlying the pharmacological actions and optimize formulation strategies for enhanced bioactivity and therapeutic outcomes. Also, there is a pressing need to validate the ethnobotanical uses of F. religiosa through rigorous pharmacological and clinical studies. While traditional knowledge provides valuable insights into the medicinal properties of the plant, scientific validation is essential toits efficacy and safety for clinical applications. In addition to pharmacological research, exploring the ecological and conservation aspects of F. religiosa is also important for its sustainable utilization.

10. CONCLUSION:

Through the extensive examination of ethnopharmacological data, it is very evident that F. religiosaisa medicinally rich and ecologically important speciesin various regions across the globe. Ethnobotanical studies have revealed the diverse traditional uses of F. religiosa. These traditional practices have provided a foundation for further scientific investigations, leading to the identification and characterization of numerous bioactive compounds from different parts of the plant. The pharmacological studies highlighted in this review have demonstrated the promising therapeutic potential of F. religiosa extracts and isolated compounds in managing various health conditions, including diabetes, inflammation, microbial infections, cancer, etc. Moreover, the pharmacological activities of F. religiosa are due to its rich phytochemical profile, which includes phenolics, terpenoids, alkaloids, flavonoids, and other secondary metabolites. Ultimately, F. religiosa emerges as a promising candidate for drug discovery and development, offering a wide spectrum of bioactive compounds with diverse pharmacological activities. By implementing traditional knowledge with modern scientific advancements, F. religiosa holds the potential to make significant contributions to the field of natural medicine and healthcare.

11. CONFLICT OF INTEREST:

All the authors declare no conflict of interest.

12. ACKNOWLEDGEMENT:

We are highly thankful to the Dean and Professor Dr. Ajay Singh, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun for providing the necessary facilities during the study.

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Plant Parts	Therapeutic Efficacy	Potential Bioactive Compounds	References
1. Fruit (Fig)	Constipation, asthma, diuresis, fever and fractures	Chlorogenic acid, ellagic acid, gallic acid, kaempferol, linoleic acid, oleic acid, palmitic acid, quercetin, rutin, β-amyrin andβ-sitosterol	9,16
2. Latex	Cough,asthma, tumors,warts, skin infections, nepheroprotection, neuralgia and inflammation	Ficin and sesquiterpene	9,17,18
3. Seed	Diabetes, arthritis, bowel-related disease, infections caused by bacteria,virusesor fungi, wound healing, cancer, gastrointestinal disorder and refrigerant	Apigenin, friedelin, kaempferol, lupeol, luteolin, quercetin, stigmasterol, α-amyrin acetate, β-amyrin acetate and β-sitosterol	9,19
4. Leaf	Diabetes, digestive issues, epilepsy, eye ailments, inflammation, skin diseases, wound healing, asthma, cough, sexual disorder and wounds	Ascorbic acid, Ellagic acid, Ficuseptine,Gallic acid, Kaempferol, Lupeol, Luteolin, Oleanolic acid, Quercetin, Ursolic acid, β-Sitosterol, β-sitosterol and β-sitosterol glucoside	9,20
5. Bark	Blood sugar control, diarrhea, dysentery, respiratory problems, nephroprotective, wound healing, cooling, skin diseases, vomiting, inflammation and burn	Betulinic acid, oleanolic acid, ursolic acid and β-sitosterol	9,21,22,23,24
6. Root	Diuresis, jaundice and kidney stone	Phenolicsglycosides, saponins and tannins	9,25