The Multifaceted Benefits of Triphala: Uncovering Phytochemical and Pharmacological Properties From Antiquity to Modern Times.

Most Ayurvedic drugs are polyherbal formulations. Amongst Triphala, a widely utilised Ayurvedic formulation, is available globally as a health promoting agent. It consists of more than 150 bioactive compounds that work synergistically and restore the physiological balance. The term Triphala implies the meaning of three fruits, that is, Tri—three, Phala—fruit. The outer pericarp of the fruits of Haritaki (Terminalia chebula), Vibhitaki (Terminalia bellirica), and Amalaki (Emblica officinalis) is grouped as Triphala. It is indicated in the treatment of a wide disease spectrum, like pyrexia, integumentary disease, diabetes mellitus, wound healing, dentistry, angiogenesis, arthritis, protection against radiation, cancer, and so forth. The multidimensional health benefits of Triphala are mainly due to the presence of several phytochemicals like ellagic acid, chebulinic acid, gallic acid, corilagin, and so forth. However, only a few comprehensive reviews have been published on the phytochemistry and pharmacology of Triphala so far. Therefore, in this review, we have provided an in‐depth exploration of Triphala, tracing its reported uses from ancient Ayurvedic traditions to modern scientific understanding. We have discussed its key bioactive molecules, presented evidence of its diverse pharmacological activities, examined its relevance to current disease groups, and outlined future research directions in detail.

pharmacology, phytochemicals, polyherbal formulations, Triphala The review article highlights the traditional uses of Triphala in treating a variety of ailments, including fever, skin diseases, diabetes mellitus, wound healing, dental issues, angiogenesis, arthritis, protection against radiation, and cancer, among others. Furthermore, the article addresses the presence of key bioactive molecules in Triphala, providing evidence of its diverse pharmacological activities. Abbreviations - 3T3‐L1 cell line 3T3‐Swiss albino fibroblast cell line - 5‐HT 5‐hydroxytryptamine or serotonin - 60Co cobalt - AH26 dental epoxy resin sealer - AKT/PKB protein kinase B - ALP/SGPT alkaline phosphatase - ALT alanine transaminase - AST/SGOT aspartate transaminase - ATP adenosine triphosphate - Bax Bcl‐2 associated X‐protein - Bcl‐2 B‐cell lymphoma 2 - BDNF brain‐derived neurotropic factor - BUN bun urea nitrogen - c/EBP—α transcription factor CCAAT/enhancer binding protein - Ca2+‐ATPase calcium‐adenosine triphosphatase - CAD coronary artery disease - cAMP cyclic adenosine monophosphate - CD3 cluster of differentiation 3 - CD31 cluster of differentiation 31 - CD4‐T cluster of differentiation 4 T cells - CD8 cluster of differentiation 8 - CFU colony forming unit - c‐Myc/Cyclin D1 nuclear receptor β‐catenin protein - COX‐2 cyclooxygenase‐2 - CXCL‐10 C‐X‐C motif chemokine ligand 10 or interferon gamma‐induced protein 10 - CYP1A human cytochrome P450 1A - CYP2D6 cytochrome P450 2D6 - CYP3A human cytochrome P450 3A - CYP3A4 cytochrome P450 3A4 - EGFR epithelial growth factor receptor - ERK extracellular signal regulated kinase - ERp36 endoplasmic reticulum protein 36 and 29 - FAS fatty acid synthase - FGF fetal growth factor - GFR glomerular filtration rate - GIP glucose‐dependent insulin‐promoting polypeptide - GLP‐1 glucagon‐like peptide‐1 - GLUT‐4 glucose transporter‐4 - GPx glutathione peroxidase - GSH reduced glutathione - GST glutathione S‐transferase - Gy/min gray/min - HBV hepatitis B virus - HDL high‐density lipoprotein - HIV human immunodeficiency virus - HIV‐RT HIV‐1 reverse transcriptase - HPDE‐6 normal human pancreatic ductal epithelial cells - IFN‐γ interferon gamma - IL‐1β interleukin‐1β - IL‐10 interleukin‐10 - IL‐2 interleukin‐2 - IL‐6 interleukin‐6 - JNK Janus kinase - Ki67 cells proliferation marker - LDL low density lipoprotein - MAPK mitogen‐activated protein kinase - MCP‐1 monocyte chemoattractant protein‐1 - MEK1/2 human MAP kinase kinase 1/2 - Mg2+‐ATPase magnesium‐adenosine triphosphatase - MMP‐2 matrix metalloproteinases - Na+‐ATPase sodium‐adenosine triphosphatase - NAC N‐acetyl cysteine - NaOcl sodium hypochlorite - NF‐κβ nuclear factor kappa‐light‐chain‐enhancer of activated B cells - OGTT oral glucose tolerance test - p.o. per oral - P38 protein 38 - phosphor‐p44/42 phosphorylated protein 44/42 - PKA protein kinase A - PMN‐type polymorphonuclear leukocytes - PPAR‐γ peroxisome proliferator‐activated receptor - ROS reactive oxygen species - SCID severe combined immunodeficiency disease - SOD1 superoxide dismutase - sp. species (singular) - spp. species (plural) - TA100 ester strains of S. typhimurium base pair substitutions - TA98 esters strains of S. typhimurium frame shift mutation - TGF‐β tumor growth factor‐β - Thr‐202/Tyr‐204 threonine 202/tyrosine 204 - TNF tumor necrosis factor - TXNIP liporin protein interaction protein - U0126 highly selective inhibitor of MEK 1 - VEGF vascular endothelial growth factor - VEGFR vascular endothelial growth factor receptor - Wnt/β‐catenin cell surface receptors in cell signaling pathways - ZO‐1 zonula occludens‐1 1. Introduction In the vast landscape of traditional medicine, certain remedies stand out for their enduring legacy and profound impact on human health. Triphala, a trinity of fruits deeply rooted in the ancient wisdom of Ayurveda, emerges as one such timeless gem, offering a holistic approach to wellness that transcends the boundaries of time and culture. The origins of Triphala can be traced back to the Ayurvedic text Charaka Samhita, where it is hailed as a panacea for a multitude of ailments. The Triphala later made its way to China via the Silk Road, where it gained traction as a complementary and alternative therapy for chronic conditions. It is now extensively used throughout East Asia. Furthermore, traditional healers laud Triphala as a potent health tonic renowned for its purifying, rejuvenating, and body‐balancing properties [1, 2]. The term Triphala implies the meaning of three fruits, that is, Tri—three, Phala—fruit. The outer pericarp of the fruits of Haritaki (Terminalia chebula), Vibhitaki (Terminalia bellirica), and Amalaki (Emblica officinalis) is grouped as Triphala. It embodies the essence of balance and harmony, principles central to Ayurvedic philosophy. Each component of Triphala brings forth unique therapeutic properties, synergistically blending to create a potent elixir for holistic health. For instance, Amalaki, also known as Indian gooseberry, serves as the cornerstone of Triphala, revered for its rich reservoir of vitamin C and potent antioxidant activity [3]. Beyond its immune‐boosting prowess, it profoundly influences digestive health, aiding in the assimilation of nutrients and promoting regularity [4]. Vibhitaki, characterized by its astringent taste, complements Amla's actions with its tonic and rejuvenating effects on the gastrointestinal tract [5]. Its ability to pacify excess Kapha, one of the three doshas in Ayurveda associated with mucus production and congestion, makes it invaluable in addressing respiratory and digestive concerns [6]. Haritaki, the crown jewel of Triphala, reigns supreme with its cleansing and detoxifying ability, revered as the “king of herbs” in Ayurveda. Haritaki boasts a myriad of benefits, ranging from promoting healthy elimination to rejuvenating cellular function [7]. Triphala is used as a major drug in many disease conditions in varying ratios of its raw drugs as 1:1:1, 1:2:4, and 1:2:3, and Triphala water is prescribed as a vehicle along with other drugs in various diseases. While the ancient sages extolled the virtues of Triphala through the ages, modern science has begun to unravel its mysteries, shedding light on its diverse therapeutic potential. Research studies have corroborated Triphala's efficacy in promoting gastrointestinal health, enhancing immune function, and exerting antioxidant and anti‐inflammatory effects [6, 8, 9]. In addition to its physical benefits, Triphala is revered for its adaptogenic properties, helping the body adapt to stressors and maintain homeostasis [10]. Its gentle yet profound cleansing action makes it a popular choice for detoxification regimens, offering a natural alternative to harsh cleanses [11]. In an era marked by the resurgence of interest in natural remedies and holistic wellness, Triphala stands as a beacon of hope, offering a safe and effective solution for modern‐day maladies. Whether seeking relief from digestive discomfort, bolstering immunity, or embarking on a journey of detoxification and rejuvenation, Triphala holds the promise of transformation, aligning body, mind, and spirit in a harmonious union as we traverse the ever‐evolving landscape of health and wellness. Because of its importance, Triphala is used as a popular ingredient in various Ayurvedic formulations such as Triphaladi Churnam, Triphala Ghrita, Mahatraiphala Ghrita, Navayasa Churnam, Mandura Vataka, Punarnava Mandura, Mahavajraka Ghritam, Vajraka Tailam, Anutailam, Tryushanadi Ghritam, Hapushadi Churnam, Mahatiktaka Ghritam, Kalyanaka Ghritam, Eladi Lehyam, Phalasarpi, Tilvaka Ghritam, and so forth [9]. The pharmacodynamic properties of Triphala are mentioned below The pharmacodynamic properties (Rasa Panchaka) of Triphala are Rasa (taste): Five tastes devoid of salty taste (Pancharasa Lavana rahita) Guna (property): Light, Dry (Laghu, Ruksa) Virya (potency): Hot (Ushna) Vipaka (taste after bio transformative phase): Sweet (Madhura) Dosha karmukata (effect on dosas): Kapha‐Pittahara Prabhava (specific action): Tridosha hara, Rasayana In recent years, there has been an increasing number of scientific publications focused on Triphala. According to PubMed, there are currently 306 references available on Triphala. The first article on Triphala was published in 1963, but significant research did not begin until 2000. Since then, extensive research has been conducted on Triphala drugs. Despite the pandemic in the past 5 years alone, a substantial amount of research has emerged on the topic, with 128 papers being published covering various aspects of Triphala. However, there has not been a comprehensive review of experimental studies that explores the mechanisms of action of Triphala against various diseases. This review aims to provide detailed information on Triphala phytoconstituents and its therapeutic applications in treating different diseases from a mechanistic perspective. 1.1. Various Forms of Triphala The Triphala formulation is available in various forms, such as ghrita, churna, kwath churna, ointment, syrup, tablet, oil, capsule, toothpaste, and so forth, for various treatments. It can be taken with different media for multiple purposes. Some of them are mentioned below in Figure 1. Here, Vata diseases are related to neuromuscular disorders, joint disorders, and so forth. Pitta diseases are related to stomach ulcers, stomatitis, piles, and so forth, and Kapha diseases are like respiratory and digestive disorders. 2. Review Method In the initial step of our research, we conducted a detailed literature search to evaluate whether any systematic reviews have addressed the phytochemical and pharmacological properties of Triphala for various health benefits, spanning from ancient times to the present. Our findings revealed that only a few comprehensive reviews are available, which have not been discussed in detail in a mechanistic way. This indicates a gap between the phytochemistry and the pharmacological applications. Therefore, this review aims to provide extensive coverage of Triphala reported from ancient times to the present day from the Ayurvedic perspective. To achieve this, we performed an in‐depth literature survey using various keywords such as “Triphala,” “pharmacological applications,” “polyphenols,” “polyherbal formulations,” “phytochemicals,” and so forth. The search strategy involved several prominent databases, including PubMed, Scopus, and ScienceDirect. In this process, initially we collected 885 results, which comprised research articles, review articles, mini reviews, book chapters, short communications, case studies, and so forth, spanning years 1963–2025. From this, we selected 410 indexed references that dealt mainly with Triphala, of these, we used 206 major references in the present article. We omitted 125 references due to duplication of articles from different sources. Excluded articles include those with unavailable full‐text content, as well as articles not related to the therapeutic domain of Triphala and novel drug delivery therapeutic approaches. The review method is shown as a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram in Figure 2. 3. Phytochemical Investigation The literature studies found the presence of carbohydrates, phenolic acids, tannins, steroids, terpenoids, alkaloids, flavonoids, cardiac glycosides, oils, saponins, coumarins, gum, and mucilage in different extracts of Triphala [12, 13, 14, 15, 16]. Primarily, phenolic compounds are of great importance as cellular support material because polymeric phenols form an integral part of the cell wall structure [17]. Bioactive polyphenols are particularly noteworthy as they can protect the human body from oxidative stress, which is associated with various diseases such as cancer, cardiovascular issues, and aging [18]. Tannins play a role in protecting plants from predation and pesticides, as well as in plant growth regulation. Previous studies by various researchers have shown that flavonoids provide health benefits through cell signaling pathways and antioxidant effects [12]. Various phytoconstituents of Triphala are mentioned in Figure 3. 3.1. Chemical Characteristics of Triphala Triphala, a cornerstone of Ayurvedic medicine, has an efficiency that originates from its varied spectrum of phytoconstituents, about 150 in total, each of which contributes uniquely to its biological activities. Some of the significant applications of phytoconstituents of Triphala are listed below. Melissic acid (triacontanoic acid) is a long‐chain fatty acid that exhibits significant inhibitory activity against Clostridium perfringens and Escherichia coli, suggesting its potential in combating gastrointestinal infections. Its mechanism of action likely involves disrupting bacterial cell membranes, making it a valuable component in Triphala's antimicrobial arsenal [19]. Syringic acid is a naturally occurring phenolic compound, and it is an ether derivative of gallic acid. It is known for its antiradical activity; syringic acid scavenges free radicals, mitigating oxidative stress and protecting cellular structures from damage. Its inclusion in Triphala enhances the formulation's antioxidant capacity, which is crucial for maintaining cellular health and combating various chronic diseases [20]. Ellagic acid is a polyphenolic compound known for its anti‐proliferative activities, it holds promise in cancer prevention and treatment. By inhibiting the growth of cancer cells and inducing apoptosis, it exhibits potential as an adjunctive therapy in oncological interventions. Within Triphala, ellagic acid synergizes with other constituents to bolster its anticancer effects [21]. Punicalagin is also a polyphenolic compound; it has potent antifungal properties that reinforce Triphala's efficacy against fungal infections, including candidiasis and dermatophytosis. By disrupting fungal cell membranes and inhibiting key enzymes, it offers a natural alternative to conventional antifungal agents, potentially with fewer side effects [22, 23]. Ascorbic acid (vitamin C) is not only a potent antioxidant but also plays a vital role in immune function. Within Triphala, it enhances the formulation's antiviral and immunomodulatory activities, bolstering the body's defense mechanisms against viral infections and supporting overall immune health. Chebulagic acid is a benzopyran tannin with demonstrated antiviral activity; it adds another layer of defense against viral pathogens within Triphala. By inhibiting viral replication and attachment, it shows promise in the management of viral illnesses, including influenza and herpes infections [24]. Punigluconin is an ellagitannin, a polyphenol compound. This compound exhibits notable antitumor activity, suggesting its potential role in cancer prevention and therapy. Through various mechanisms, including apoptosis induction and cell cycle arrest, punigluconin contributes to Triphala's holistic approach to cancer management [25]. Quercetin is a flavonoid renowned for its antimicrobial properties; quercetin enhances Triphala's ability to combat microbial infections. By inhibiting the growth of bacteria and fungi, it addresses various infectious diseases, from urinary tract infections (UTIs) to skin infections [26]. Gallic acid is a phenolic acid that has potent anti‐inflammatory activity. It mitigates inflammation and associated symptoms within Triphala. By inhibiting proinflammatory cytokines and enzymes, it offers relief from conditions such as arthritis, gastritis, and inflammatory bowel disease [27]. Isostrictiniin is a polyphenol compound that exhibits protective effects against oxidative stress and cellular damage. Within Triphala, isostrictiniin enhances the formulation's overall health‐promoting properties, contributing to its efficacy in preventing age‐related diseases and promoting longevity [28]. Corilagin is an ellagitannin known for its antitumor activities. Corilagin shows promise in cancer therapy. By inhibiting tumor cell proliferation and angiogenesis, it complements Triphala's multifaceted approach to cancer management, offering new avenues for treatment [29]. Mannitol is a compound that influences dehydrogenase activities and plays a crucial role in cellular metabolism and energy production. Within Triphala, it contributes to the formulation's metabolic effects, supporting overall health and vitality [30]. β‐Sitosterol is a phytosterol that exhibits potent anti‐inflammatory properties, making it valuable in managing inflammatory conditions within Triphala. By modulating immune responses and reducing inflammation, β‐sitosterol enhances the formulation's efficacy in alleviating various inflammatory disorders. The rich tapestry of phytoconstituents within Triphala underscores its profound therapeutic potential. From combating infections to mitigating inflammation and inhibiting tumor growth, Triphala offers a holistic approach to health and wellness. Further research into its mechanisms of action and clinical applications promises to unveil new vistas in integrative medicine, harnessing the power of nature to promote human health and vitality [31]. 4. Safety and Toxicity of Triphala Herbal formulations have been used since ancient times, so ensuring their safety is vital for consistent usage. Triphala did not show any toxic effects up to 240 mg/kg in vitro [32] and ex vivo studies (Artemia nauplii species) [33]. In rodents, an acute oral toxicity study, up to 5000 mg/kg and in chronic oral administration, up to 2400 mg/kg for 270 days, did not show any pathological changes in the physiology of the test system [34]. Extracts of ethanol, water and the oral formulation Triphala Mashi up to the dose of 1750 mg/kg [35] and aqueous extract up to the dose of 240 mg/kg (intraperitoneal route) were proved safe in acute toxicity [36]. On clinical evaluation in healthy individuals, intake up to the dose of 2500 mg/day for 28 days and ethanol extract (1050 mg/day) thrice daily for 14 days, did not report toxicological symptoms, only observed adverse effect was constipation in a few patients, others reported good bowel function with a significant increase in cytotoxic T cells and natural killer cells (CD16+ and Cd56+) and no significant fluctuations in liver and renal enzymes were reported [32, 34, 35, 36, 37, 38, 39, 40, 41]. 4.1. Pharmacokinetics of Triphala in the Body The pharmacokinetics of Triphala, particularly regarding its intestinal absorption, reveal critical insights into how its bioactive components are processed in the body. 4.1.1. Absorption Triphala decoction, particularly when processed with honey, revealed significant insights into its absorption and efficacy. Higher intestinal absorption was observed in processed Triphala decoction with honey due to its rich polyphenol content. Some of the formulations, like Triphala Kashaya Samskaritha madhu, showed about 67.8%, and Triphala Kashaya Mishrita Madhu had about 6.8% absorption in the intestine [38]. Gallic acid showed higher absorption in the intestine than ellagic acid, and it also inhibited first‐pass metabolism in the liver [42], and it increases the bioavailability in the systemic circulation. 4.1.2. Metabolism Triphala (500 mg/kg) was an enzyme inhibitor, which inhibited cytochrome P450 enzymes like CYP3A (androstenedione 6‐beta hydroxylase enzyme), CYP1A [43] and also includes CYP3A4 and CYP2D6 [44]. Its metabolism was through the biosynthesis of phenylalanine, tyrosine, and tryptophan, metabolism of Vitamin B6 and phenylalanine, glyoxylate and dicarboxylate, sulfur, nicotine and nicotinamide, glycerophospholipid, citrate cycle, arginine and proline, tryptophan and pentose and glucuronate interconversions [42]. 4.1.3. Drug–Drug Interactions Studies reported that Triphala interacts with medications like phenacetin (an analgesic) and midazolam (an antiseizure and antianxiety drug). Simultaneous administration of phenacetin/midazolam with Triphala extract inhibits CYP1A and 3A activities and increases the bioavailability of phenacetin and midazolam [45]. Since the drug Triphala has an inhibitory action on cytochrome P450 enzymes like CYP3A4 and CYP2D6 on co‐administration with other drugs, including Tamsulosin (a drug for benign prostatic hypertrophy), Oxycodone (a kind of opioid analgesic drug), and Tilidine (a kind of opioid analgesic drug), care has to be taken to avoid toxicological effects in patient [46]. 4.1.4. Influence on Gut Microbiome Gut microbiota plays a vital role in maintaining homeostasis of physiological function, and an imbalance in the microbiome results in pathological changes in physiology through acting on the gut–brain axis. Polyphenols in Triphala can modulate the human gut microbiota by promoting the growth of beneficial Bifidobacterium and Lactobacillus species, which modulate phytoconstituents (ellagic acid, chebulinic acid) in the human intestinal microbiota into various active metabolites, like urolithins, which modulate the inflammatory process by generating anti‐inflammatory compounds and thus, prevent oxidative damage of enterocytes [47]. In obesity and cognitive disorders, imbalance in the gut microbiome was rectified on treatment with Triphala and decreased accumulation of disease‐modifying bacteria like Bacteriodetes and Verrucomicrobiota and decreased cyanobacteria in feces. It has also reduced the level of amyloid beta (plaque) accumulation in the brain, and increased gut transition time and butyrate levels [48]. In obese patients, Triphala modulates a higher prevalence of microbes like Firmicutes and Proteobacteria and a lower abundance of Bacteroides [49]. The phylum Bacteroides contributes acetate and propionate, whereas Firmicutes have butyrate as their end products. These compounds mediate fatty acid oxidation and appetite pathways and lead to anti‐obesity activity. Hydrolyzable tannins could decrease the relative abundance of Vibrio and Carboxylia virga in the gut microbiota of Pacific white shrimp [50]. A double‐blind randomized placebo‐controlled pilot study in healthy volunteers treated with 2000 mg of Triphala per day reduced the relative abundance of five Clostridium sp., three Ruminococcus spp., two Alistipses spp., Blautia spp., and Eisenbergiella spp. [51] The constituents, like gallic acid and quercetin, also reported that they promote beneficial gut microbes like Lactobacillus sp. and Bifidobacteria sp. [37]. In healthy individuals, a balanced gut microbiota Firmicutes to Bacteroidetes ratio, A. cinephilia, from the family of Verunuco microbiota, and the relative abundance of six Clostridium spp., three Bacteroides spp., three Eubacterium spp., Citrobacter spp., Coprococcus spp., Lactobacillus spp., Prevotella spp., and Roseburia spp. will be high [51]. The combination of Triphala and medicated honey may synergistically improve health outcomes, particularly in digestive and metabolic disorders [52]. Triphala extract modulated the simulated colonic microbiota by promoting the proliferation of Akkermansia muciniphila while suppressing the Bifidobacterium species. Metabolomic analysis revealed an elevation in phenolic compounds and antioxidant capacity, alongside a reduction in fermentation‐derived metabolites such as ammonia, valeric acid, isovaleric acid, and isobutyric acid, changes that may support improved intestinal function, particularly under constipated conditions. Furthermore, the fermentation products attenuated transcriptional activity of the aryl hydrocarbon receptor (AhR), mediated by polyphenol constituents [51]. 5. Pharmacological and Biological Effects of Triphala Various pharmacological effects of Triphala are mentioned in Table 1 and explained one by one in detail. TABLE 1. | Parts of the physiological system | Treatment | Mechanism of action | References | |---|---|---|---| | Effect on the central nervous system | Memory impairment disorders like dementia, Alzheimer's disease, catalepsy | Immunomodulation, regulation of neurotransmitter balance and antioxidant enzyme synthesis | [53, 54] | | Effect on cardiovascular system | Hypertension, coronary artery disease | Decreasing LDL and improving HDL levels | [55] | | Effect on pulmonary system | Allergic rhinitis, bronchial hyperactivity, pharyngitis | Activation of immunity and antioxidant balance | [56, 57, 58] | | Effect on the gastrointestinal system | Hyperacidity, gingivitis, periodontitis, oral submucous fibrosis, dental caries, malabsorption, constipation, diarrhea, ulcer, nonalcoholic fatty liver disease, colitis | Improving antimicrobial, antioxidant properties, modulation of the inflammatory pathway and ion channels | [59, 60, 61, 62, 63, 64, 65, 66, 67] | | Effect on the excretory system | Nephrotoxicity, urolithiasis, urinary tract infection | Improving antimicrobial and antioxidant properties | [68, 69, 70, 71, 72] | | Effect on the endocrine system | Diabetes, obesity | Inhibiting insulin resistance | [18, 32, 49, 73, 74, 75] | | Effect on the integumentary system | Seborrhea, skin aging, wound | Improving antioxidant and antimicrobial properties | [37, 76, 77, 78, 79, 80, 81, 82, 83] | | Effect on the reproductive system | Leucorrhea, polycystic ovarian disease, hormonal imbalance, fertility | Regulation of hormonal synthesis | [84, 85, 86] | | Effect on ophthalmic system | Cataract, uveitis, dry eye syndrome, computer vision syndrome, proliferative vitreoretinopathy | Improvement of antioxidant enzyme synthesis | [21, 46, 87, 88, 89, 90] | | Effect on the immune system | Inflammatory disease—arthritis Microbial disease—HIV, septicemia Cancer—Liver, stomach, colon, brain, breast, endometrium, prostate, ovarian, pancreas, and lymph node Vector‐borne disease—Dengue, malaria Others—Lipoma, arthritis | Activation of the apoptosis pathway in the cell cycle | [91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105] | 5.1. Effect on the Central Nervous System Catalepsy, a neurological disorder marked by rigidity, immobility, and inflammation, can result from medications like haloperidol and chlorpromazine. The polyherbal formulation Triphala NR‐ANX‐C has shown anti‐cataleptic effects by modulating inflammatory mediators, impacting both innate and adaptive immune responses, including cytokine production, neutrophil function, and lymphocyte activity [53]. It also increases the antioxidant enzymes, decreases the neurobehavioral changes, regulates the MAPK signaling pathway (p‐Erk1/2, p‐JNK1/2, and p‐p38) and decreases neuronal membrane damage [106] on intake of Triphala (1 g/kg/bw) for 48 days [107, 108]. In cardiocerebrovascular disease, pretreatment with 20–80 µg/mL Triphala significantly improved the condition by inhibiting the expression of PTGS2, MMP9, and interleukin‐6 (IL‐6) [109]. 5.1.1. Antinociception Triphala exhibits anti‐nociceptive activity at an oral dose of 1200 mg/day in rodents. Antinociception means inhibiting the sensation of pain induced by sensory neurons through the release of endogenous substances like endorphins [110]. 5.1.2. Immunomodulation and Alzheimer's Diseases Alzheimer's disease (AD) is a neuroinflammatory disorder, highly influenced by gut dysbiosis (Figure 4), that is, multiple pathogens like spirochetes, oral bacteria, herpes viruses, and fungi were identified in patients and chronic activation of the innate immune system [2]. Microglia, the immune cells of the central nervous system, play a crucial role in the pathophysiology of AD. The free radicals are responsible for causing inflammation by stimulating the release of cytokines such as IL‐1, TNF‐α, and IFN‐β, which stimulate additional neutrophils and macrophages at the site of inflammation. Triphala improves memory by activating the antioxidant‐related signaling pathways, maintains the gut microbiota balance, and regulates neurotransmitter synthesis like serotonin and brain‐derived neurotropic factor, thus synergistically modulating the neuronal and synaptic functions [111]. At nerve endings, Triphala inhibits α‐synuclein fibrillation at 2.5 mg/mL, thus preventing neurodegeneration and neuroinflammation [112]. Microglial efferocytosis is an important mechanism for clearing apoptotic cells and cellular debris, facilitating the resolution of neuroinflammation. Triphala (1 g/kg/bw for 48 days) also enhances the neutrophils and phagocytic function of macrophages and decreases corticosteroid levels [113]. Another reported that Triphala intake for about 2 weeks activates CD3− and CD8++ in cytotoxic T cells and CD16+ and CD56+ in natural killer cells. It also improves innate and humoral immunity by increasing the B lymphocytes, like CD19+ and CD45+, in Alzheimer's patients. Triphala also combats stress‐induced neuroinflammation by regulating the humoral cell‐mediated immune response, complement activity, and mitogen‐activated phytohaemagglutinin induced T‐lymphocyte proliferation. Similarly, in the noise (100 dB/4 h) induced stress model, the levels of inflammatory mediators like neutrophils, TNF‐α, cytokines, interferons, IL‐2, and IL‐4 were high, and CD4+/CD8+ lymphocyte phenotype in the spleen was less, and also suppressed cell‐mediated immune response [106]. This condition was reversed on dose‐dependent oral administration (250–1000 mg/kg/day) of Triphala for 48 days [91]. FIGURE 4. Activity of Triphala on Alzheimer's disease. Another pathological immune reaction is delayed type hypersensitivity, which occurs in two phases: (i) Sensitization (induction of phagocytosis) and (ii) The effector phase (subsequent encounter of antigen and TH1 cells releases a range of cytokines which aid in the activation and recruitment of macrophages and other nonspecific inflammatory mediators) represents the immunostimulatory effect in response to T‑cell‑dependent antigen. Triphala (500 mg/kg p.o.) treated delayed type hypersensitivity [53]. 5.2. Effect on Cardiovascular Health Antioxidant, anti‐inflammatory, and lipid‐lowering properties contribute to Triphala's potential in preventing cardiovascular diseases. Increased blood levels of lipids and lipoproteins, or hyperlipidemia, are one of the risk factors for coronary artery disease (CAD). While many factors, including age, family history, a diet high in fat and cholesterol, and hypertension, are thought to have a significant role in heart failure, coronary heart disease is mostly caused by excessive cholesterol, namely, low‐density lipoprotein (LDL). Triphala reduced total cholesterol, LDL, very low‐density lipoprotein (VLDL), high‐density lipoprotein (HDL) and free fatty acid levels in the physiological system [114]. Ingredients like E. officinalis protect and mediate the hemodynamics and contractile function of the heart due to its antioxidant properties [55]. T. chebula prevents myocardial necrosis and inhibits changes in the heart's mitochondrial ultrastructure and function [115, 116]. It exhibits negative inotropic and chronotropic effects on the heart muscle [75]. T. bellirica mitigates myocardial injury, indicated by a decrease in creatine kinase‐muscle/brain [117]. 5.3. Effect on the Respiratory System 5.3.1. Management of COVID‐19 Triphala was rich in polyphenol content, which contributes to combating respiratory disorders. Long COVID is characterized by persistent symptoms associated with chronic inflammation and oxidative stress. While high‐intensity interval training (HIIT) and supplementation with antioxidants such as Triphala (1000 mg/day) for 8 weeks increased antioxidant biomarkers and reduced inflammation, oxidative stress, and dyspnea in individuals with long COVID [118]. 5.3.2. Reduction of Bronchial Hyperactivity and Chronic Pharyngitis Triphala inhibits the release of inflammatory mediators like IL‐10 and CD4 T lymphocyte cells in lungs and treats bronchial hyperactivity/ asthma. It also balances the multiorgan shift of CD4 cells and natural killer T cells. Lymphocyte redistribution in the liver, lung, and spleen was associated with decreased lung reactivity as well as decreased lymphocytic infiltration [57]. Similarly, in pharyngitis, Triphala (0.84 g/kg) intake for 5 days inhibited the formation of inflammatory promediators [58]. 5.3.3. Allergic Rhinitis It consists of two phases: an early and a late response. IgE‐mediated mast cell degranulation is a hallmark of the early phase, which begins minutes after allergen contact. Sneezing, rhinorrhoea, and nasal congestion are among the acute symptoms brought on by the production of inflammatory mediators such as histamine, leukotrienes, and prostaglandins. The activation of inflammatory cells (eosinophils, neutrophils and T cells) and the release of cytokines occur during the late phase, which begins 4–6 h after allergen exposure and lasts up to 24 h. This results in tissue remodeling and chronic inflammation. Nasal hyperresponsiveness and the emergence of other illnesses, like sinusitis and otitis media, can also be attributed to this persistent inflammation [119]. Triphala reduced the production of proinflammatory cytokines like TNF‐α, IL‐1β, IL‐6, and COX‐2. The mechanisms involved are inhibition of NF‐κB and modulation of the TH1/TH2 balance. Triphala appears to enhance TH1 cytokine levels (interferon gamma [IFN‐γ] and IL‐2) while reducing TH2 cytokines (IL‐4). This shift towards TH1 dominance could potentially counteract the TH2‐mediated inflammation in allergic rhinitis [56]. 5.4. Effect on the Gastrointestinal System 5.4.1. Effect on the Oral System 5.4.1.1. Anticaries, Anti‐Plaque, and Control Bleeding Triphala has been playing a major role in maintaining oral hygiene [120]. Dental caries is caused by the microorganisms Streptococcus mutans, Streptococcus salivarius, and Streptococcus mitis, which form biofilm and lead to dental plaque formation. S. mutans metabolizes sucrose in the mouth into dextran. This insoluble sticky glucan promotes the adherence of the microbial species on the tooth surface, thus forming dental plaque. Prolonged accumulation of dental plaque on the tooth surface results in decalcification of enamel, thereby initiating dental caries. Aqueous extracts of Triphala mouth rinse reduced total bacterial load and total streptococcal count in saliva samples for up to 3 h [60]. Many randomized controlled trial (RCT) trials in children and adults were carried out, which revealed inhibitory effects on plaque accumulation, chronic gingivitis, and growth of S. mutans, S. mitis, Staphylococcus intermedius, Streptococcus oralis, Actinomyces viscosus, Actinomyces naeslundii, Streptococcus sanguinis, and Lactobacillus [11, 59, 61, 121], and in the other clinical trial, the combination of Triphala and Ela decoction (Elettaria cardamomum) cured gingivitis and plaque formation similar to that of chlorhexidine mouthwash [62, 122]. One of the major defects in Chlorhexidine usage is staining of teeth, the same was not observed in Triphala usage [120], which acts as a good alternative and is economically cheaper [123, 124]. Triphala demonstrated superior adhesive bond strength to caries‐affected dentin, indicating its potential utility as an effective cavity disinfectant in restorative dental procedures [125] 5.4.1.2. Anti‐Periodontitis Matrix metalloproteinases (MMPs) are calcium‐dependent zinc‐containing endopeptidases that play a central role in the physiological and pathological remodeling of periodontium, their imbalance causes periodontal diseases [126]. Triphala (1500 µg/mL) inhibits the enzyme MMP‐9 present in the collagen of the extracellular matrix of the gingiva by about 76.5% in periodontitis [127, 128]. In a pilot study with 20 patients of inflammatory periodontal disease (chronic gingivitis and chronic periodontitis), usage of churna and decoction (mouth rinse) of Triphala twice daily for one month, showed decreased dental plaque with 72.7% bacterial inhibition as efficacious as Metronidazole which suggested the use of a combination of metronidazole (400 mg) and Triphala for gargling and rinsing the mouth [120, 129]. Staining of the teeth and antimicrobial resistance are common side effects of tetracycline usage, the same was not observed in the Triphala treatment [130]. 5.4.1.3. Root Canal Irrigant Root canal infections are polymicrobial, especially Gram‐negative anaerobic rods. However, Enterococcus faecalis and Candida albicans are commonly found in a high percentage of root canal failures and play a major role in the etiology of persistent periradicular lesions [131]. Ten percent Triphala, aqueous extract (50 mg/mL), and churna have potent antimicrobial activity against oral pathogens and have shown significant inhibitory activity against biofilm formation. It also does not cause cytotoxicity in human PDL fibroblast cells compared to sodium hypochlorite in vitro [132, 133]. In the RCT, the same effect was observed in 49 patients [134]. This may be attributed to the presence of tannic acid [135, 136]. 0.005% Triphala solution inhibits the reduction in dentin microhardness, thus reducing the incidence of root fractures, and also inhibits hyaluronidase and collagenase enzymes, thus combating inflammation [95, 96]. Triphala solutions of 3%, 5%, and 10% showed anti‐smear formation at the intra‐articular region of curved canals in teeth and were used as a root canal irrigant [137]. 5.4.1.4. Oral Submucous Fibrosis Triphala at 5 µg/mL reversed the sub‐mucosal oral fibrosis induced by arecoline (50 µM), a compound present in the areca nut, by inhibiting the p16 and p21 genes involved in the senescence pathway without affecting normal cell proliferation [96]. 5.4.1.5. Dental Hypersensitivity A randomized controlled clinical trial was conducted in 73 tooth sensitive people, and oral intake of Triphala juice relieved the pain and sensitivity in the teeth. Dentin hypersensitivity, more commonly known as sensitive teeth, refers to a type of dental pain. Discomfort typically arises from exposed dentin responding to heat, cold, touch, pressure, or acidic foods [138]. 5.4.1.6. Adjuvant to Root Canal Treatment In root canal endodontic treatment, commercial sealers were available that fill the tiny gaps between the primary root canal filling material and the root canal wall, which releases formaldehyde that causes cytotoxicity in gingival fibroblasts. Triphala inhibits gingival fibroblast cytotoxicity with antibacterial activity [139]. In combination with the sealer, Triphala may be used to prevent cytotoxicity. Triphala also acts as a denture cleansing agent compared to commercially available cleansers [23]. 5.4.2. Effect on Stomach Triphala aids in the maximum absorption of nutrients and the digestion of food in the stomach. It can be used as a supplement therapy for vitamin or mineral deficiencies [140]. It also cures hyperacidity and improves appetite [39]. During digestion, phenolic compounds in Triphala, like gallic acid and ellagic acid, were reported to be involved in the inhibition of lipase activity, resulting in decreased aggregation of the fat globules and long‐chain fatty acids generation, and the ellagitannins inhibit the carbohydrate digestive enzymes [2, 50, 141]. Flavonoids and total condensed tannins in Triphala stimulate adenosine monophosphate‐activated protein kinase, which optimizes lipid metabolism, adipogenesis, and increases short‐chain fatty acid accumulation [142]. Gastric ulcers are eroded open sores on the stomach's inner lining and the small intestine's upper part. About 85% of stomach ulcers were caused by Helicobacter pylori infection or long‐term use of nonsteroidal anti‐inflammatory drugs. H. pylori is a bacterium associated with many gastrointestinal diseases and gastric cancer. H. pylori relies on its urease enzyme to neutralize gastric acid and to survive in the acidic environment of the stomach. Another crucial virulence factor, cytotoxin‐associated gene A (CagA), was involved in gastric inflammation and carcinogenesis. Triphala, at the minimum inhibitory concentration of 80–320 µg/mL, was used against both standard and clinical strains of H. pylori by perturbing the microstructure of H. pylori. It also downregulated adhesion‐associated genes (alpA, alpB, babA), urease‐related genes (ureA, ureB, ureE, ureF), and flagellar genes (flaA, flaB); and inhibited bacterial adhesion, biofilm formation, urease activity, as well as CagA protein expression [64, 143]. Metabolite analysis of Triphala in biological samples revealed compounds like chebulic acid, gallic acid, corilagin, chebulagic acid, and ellagic acid. Hydroalcoholic extract of Triphala ameliorates gastric ulcers induced by indomethacin in rats via its antioxidant synthesis and by modulating ion transporters/ATPase enzymes like Ca2+‐ATPase, Na+‐ATPase, and Mg2+‐ATPase [52, 64, 65]. In vitro drug release analysis showed pectin‐coated tablets containing sennoside B and Triphala exhibit a colon‐targeted drug delivery system, which aids in inhibiting the degradation of active constituents due to the gastric acid secretions [144]. 5.4.3. Effect on Liver Triphala (300 mg/kg) is used in paracetamol overdose (500 mg/kg/day), thus preventing hepato‐renal toxicity by protecting the membrane from damage and also promoting tissue regeneration in the liver [145]. In nonalcoholic fatty liver disease patients of retrospective, controlled, open labelled series clinical study, combination of Arogyavardhini Vati and Triphala Guggulu, decreased body mass index (BMI), pain in the abdomen, nausea, vomiting, loss of appetite and burning sensation in the epigastric region were observed and also improves liver functions by decreasing the membrane damage of cells (decrease in ALT, triglycerides, and blood sugar levels) due to presence of flavonoids like lupeol, brevifolin, kaempferol and tannins like gallic acid, ellagic acid and other gallotannins [67]. Triphala helps to stimulate metabolism, improve blood circulation, and immunity [2]. 5.4.4. Effect on Intestine Triphala cleanses the colon and relieves symptoms like anorectal blockage, the sensation of incomplete evacuation, constipation, flatulence, and bloating. The aqueous and alcoholic extract of Triphala and Triphala Mashi showed a dose‐dependent (200–800 mg/kg) increase in stool consistency and reduced gastrointestinal transit time in castor oil‐induced diarrhea [35]. Triphala (540 mg/kg) treated Methotrexate induced malabsorption syndrome in cancer patients, such as folate deficiency, shortened microvilli, and induction of apoptosis in the small intestine crypts followed by a decrease in nutrient absorption in microvilli, decrease in the loss of total protein, lipids, and channels like Na+–K+ ATPase (loss of thiols and sulfhydryl groups) and also decreased the secretion of myeloperoxidase and xanthine oxidase levels in the gut mucosa [146, 147]. In a clinical study, an open‐label, prospective, interventional, and exploratory trial of the formulation “TLPL/AY/01/2008” consisting of Triphala as an ingredient in patients with functional constipation improved bowel movements and bowel evacuation after 2 weeks. Long‐term treatment with Triphala relieves the discomfort during evacuation, like pain, bloating, straining, the sensation of anorectal blockage, and no relapse of all symptoms [148]. Triphala (50 and 300 mg/kg) treated colitis by increasing antioxidant enzymes and decreasing membrane damage and inflammation at the colon site [63]. Oral administration of Triphala Guggulu (500 mg) twice daily for 6 weeks, with lifestyle interventions like intake of a high‐fiber diet with adequate water and reduced junk food intake, helped to cure bleeding piles (hemorrhoid grade I–III condition) [149]. Anal fistula is an irregular tube or tunnel that frequently forms from the anus to the skin on the outside of the anal area. A perianal abscess in the inter‐sphincteric gap and an anal gland infection (cryptoglandular infection) cause the duct to be unable to properly discharge due to the tone of the internal sphincter. As a result, the abscess tracks down and opens through a fistulous tract at the external perianal skin [150]. A study reported by Nema et al. proved that Triphala Guggulu (500 mg twice daily) with Kshara Sutra effectively treated fistula. The Kshara Sutra (application of medicated thread) is used in the cutting and healing of the fistulous tract. Kshara Sutra cuts unhealthy portions of the tract and provides simultaneous healing [151]. 5.5. Effect on the Renal System Triphala (500 mg/kg) reported nephroprotective action against bromobenzene‐induced nephrotoxicity on administration for 8 consecutive days [69]. Triphala Karpa Chooranam demonstrates significant anti‐urolithiatic activity by lowering the concentrations of oxalate, calcium, and phosphate in both urine and renal tissues, thereby inhibiting the formation of urinary calculi. In addition, it helps mitigate membrane damage, inflammation, and associated infections [71]. UTIs are commonly caused by pathogens such as E. coli, Pseudomonas, Klebsiella, Proteus, Enterococci, and Staphylococcus species. These infections often manifest as burning micturition, lower genital pain, and vaginal irritation. Triphala Kwath effectively reduces bacterial load and is beneficial in managing recurrent UTIs [152]. 5.6. Effect on the Endocrine System 5.6.1. Antidiabetes Diabetes is a metabolic syndrome characterized by hyperglycemia in the blood, which leads to several complications like nephropathy, neuropathy, and retinopathy. Chronic hyperglycemia in the nerves leads to pathological changes like demyelination of nerves, narrowing of neuronal capillaries, axonal thickening, and loss of nerve fibers. The neuronal damage can be attributed to elevated levels of oxidative stress and advanced glycation end products in nerves [153]. Another microvascular complication is diabetic retinopathy, which causes vision loss, that is, by disruption of the blood‐retinal barrier, loss of pericytes, capillary basement thickening, capillary cellularity, and microaneurysm [154, 155]. The molecular mechanism involved is activation of the polyol pathway, which was preceded by two enzymes, that is, aldose reductase and sorbitol dehydrogenase. Aldose reductase, present in the retinal cells, generally acts as a detoxifier by converting toxic aldehydes to inactive alcohols [156]. In chronic hyperglycemic conditions, aldose reductase converts glucose into sorbitol using reduced nicotinamide adenine dinucleotide phosphate as a cofactor. The rise in sorbitol causes increased sorbitol dehydrogenase activity. The increased sorbitol dehydrogenase converts sorbitol into fructose using nicotinamide adenine dinucleotide as a cofactor [155]. The increased sorbitol increases the osmotic pressure in the retinal cells, while fructose is metabolized into strong glycosylating agents, leading to the formation of advanced glycated end products and activation of the inflammatory cascade and retinal damage [157]. Upregulation of the TGF‐β leads to the accumulation of an extracellular matrix, which further increases the retinal thickness and reduces the thickness of the inner and outer nuclear layer of the retina [70]. A third complication, diabetic nephropathy, is characterized by free radical accumulation, inflammation, apoptosis, increased albumin‐to‐creatinine ratio, microalbuminuria, and decreased glomerular filtration rate [158, 159]. Triphala treats diabetes, diabesity [160] and its complications like neuropathy [161], nephropathy and retinopathy in diabetic patients [162]. It also regulates the homeostasis of the islet of β cells by activating the incretin–cAMP signaling pathway in the pancreas [99]. Triphala Churna inhibited neuronal damage, inflammation, and demyelination of neurons in neuropathy [155, 163]. In retinopathy, Triphala inhibits aldol reductase and sorbitol dehydrogenase and thereby inhibits the formation of advanced glycated end products and the inflammatory cascade, indicating its inhibitory effect on the polyol pathway. The aqueous and alcohol extracts of Triphala, which contain chebulagic acid and chebulinic acid, inhibit SMAD 3 phosphorylation to prevent mesenchymal transition in retinal pigment epithelial cells [164]. In nephropathy, Triphala regulates the renal function by its antioxidant and anti‐inflammatory properties, and it slows down the renal damage via inhibition of matrix accumulation, collagen deposition, and renal fibrosis [68]. 5.6.2. Anti‐Obesity Obesity increases the incidence of diabetes mellitus, dyslipidemia, CAD, atherosclerosis, liver cirrhosis, and neuronal disorders. The low antioxidant enzymes and high lipid profiles were found in obese patients [165]. The Triphala's role in decreasing obesity was shown in Figure 5. FIGURE 5. Anti‐obesity effect of Triphala. Triphala increases the antioxidant enzyme synthesis and modulates the glucose transporters (GLUT4) activation in adipogenesis [32]. GLUT4 expression is increased during adipocyte differentiation, and it maintains glucose homeostasis in differentiated and insulin‐responsive cells [166]. Triphala extract stimulates fatty acid β‐oxidation and inhibits adipocyte differentiation, thereby decreasing lipogenesis, increasing the process of lipolysis via downregulation of PPARγ and C/EBPα [167]. As per the reports, Triphala (1 mg/mL) activates the phenylalanine, tyrosine, and tryptophan biosynthesis, metabolism of vitamin B6, and metabolism of phenylalanine (l‐tyrosine and l‐phenylalanine), which regulates the energy metabolism and helps in obesity management [42]. Triphala Kashaya Samskara Madhu has well‐established activity in hyperlipidemia [32, 69]. Triphala dissolves accumulated fats in the body, which contains polyphenols such as phenolic compounds, flavonoids, hydrolyzable tannins, and condensed tannins. Various in vitro, in vivo, and clinical studies were carried out and validated this effect scientifically in 3T3‐L1 cell line, atherogenic, high‐fat induced, hypercholesterolemia models and in obese patients [74, 168]. 5.7. Effect on the Reproductive System Triphala treated irregular menstrual cycle, menstrual migraine [169], primary dysmenorrhea, polycystic ovarian syndrome, menopausal symptoms, premenstrual syndrome, and endometriosis. All the issues related to hormonal imbalance of estrogen, progesterone, and androgen, formation of oxidative stress, and activation of the inflammatory cascade. Triphala addressed hormonal imbalances and normalized uterine function through its antioxidant properties. It also improves fertility by maintaining hormonal balance [85], improving blood circulation [86], sperm motility and viability in males [170], and increases ovulation and its development in females. Triphala Kashaya/Kwath was used as a vaginal wash in leucorrhea patients and vulvovaginal candidiasis. Triphala has the potential to prevent female gynecological cancers by downregulating the MAPK/ERK/PI3K/Akt/mTOR/p53/NF‐κB signaling pathways. It was involved in the activation of antioxidants, apoptosis and cell cycle regulation [78, 171, 172]. 5.8. Effect on Skin 5.8.1. Anti‐Seborrheatic Activity and Psoriasis Triphala stimulates the innate immune system [40] and reverses skin aging and seborrhoea [76, 173]. In a randomized controlled double‐blind trial and a case report, oral administration of Triphala (1 g) for 8 weeks treated scalp seborrhoea by inhibiting the α‐reductase enzyme in the sebum biosynthesis [37]. In a single case study, oral administration of Triphala Kashaya and external application of Dehigetadi Lepa for 14 days relieved psoriatic burning sensation and pinpoint bleeding skin. Other psoriatic symptoms, such as dry scaling, itching, and changes in skin coloration, disappeared on treatment with Triphala [171]. Herbal prebiotic Triphala is effective in reducing scalp sebum secretion in patients with scalp seborrhea [37]. 5.8.2. Wound Healing Wound healing is the intricate process of restoring the structure and function of damaged tissues. Two categories of wounds are present: (i) acute and (ii) chronic. Acute wounds include surgical cuts, tears, and anomalies, and chronic wounds include diabetic foot ulcers, burns, pressure ulcers, and venous leg ulcers. Triphala contains various bioactive constituents like alkaloids, essential oils, flavonoids, tannins, saponins, and phenolic compounds, which are responsible for wound healing activity by exhibiting anti‐inflammatory, antioxidant, antibacterial, and pro‐collagen synthesis properties. Antioxidant balance and enzyme homeostasis progress to re‐epithelialization, cell–cell, and cell–matrix interactions. At the wound site, Triphala treatment improves cross‐linking of fibres with collagen formation (Type I collagen and Type III) [93] by inhibiting human polymorphonuclear neutrophil collagenase. It also increases hydroxyproline and gelatin content and antagonises inflammatory mediator formation like MMP‐8 and MMP‐9, thus inducing wound contraction [127]. To prevent secondary wound infections, active constituents of Triphala bind with the peptidoglycan layer of bacterial proteins, interrupting the replication of bacteria, thus preventing biofilm formation. Triphala inhibit the growth of pathogens (Staphylococcus aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa) from the wound site, but also neutralizes the free radical formation and membrane damage via restoring antioxidant balance [172, 173]. Its mechanism of action is presented in Figure 6. The experimental studies of Triphala are given in Table 2. Triphala has constituents like catechin, polyphenols [78], vitamin C and epigallocatechin gallate, which are responsible for the wound healing properties [87]. FIGURE 6. Wound healing mechanism of Triphala. TABLE 2. | S.no. | Type of wound | Treatment scheduled | Reference | |---|---|---|---| | 1. | Excision wound | Topical administration of Triphala ointment applied once daily for 12 days in the wound region | [77] | | Topical application of hydroxyapatite nanocomposites synthesized using Triphala‐derived metabolites, administered over a 21‐day period in the wound region | ||| | Topical application of 15% w/w Triphala extract, administered twice daily in the wound region | [79] | || | Topical application of Triphala extract at a concentration of 1500 µg/mL in the wound region | [80] | || | 2. | Incision wound | Topical application of 10% (w/w) Triphala extract in the affected area | [80] | | 3. | Dead space wound | Oral administration of Triphala extract (200 mg/kg w/w) for 10 days | [81] | | 4. | Diabetic foot ulcer | Combined regimen involving the topical application of Triphala Kwatha and the oral administration of Triphala Guggulu and Amrita Guggulu, each at 750 mg thrice daily, sustained over 2 months | [81, 83] | | Topical application of Triphala Kwatha once daily for 7 days in the affected area | [163, 174] | || | 5. | Full‐thickness dermal wound | Oral administration of Triphala Kwath (10–20 mL) | [82] | | 6. | Acute necrotizing fasciitis in the hands | Oral administration of Triphala Kwath twice daily (10‐20 mL) | [175] | | 7. | Episiotomy wound | Oral administration of Triphala Guggulu at a dose of 500 mg daily | [176] | | 8. | Infected wound | Topical application of Triphala ointment for 12 days in the affected area | [177] | 5.8.3. Antiaging Skin aging is caused by reactive oxygen species (ROS), physical stressors and chemicals that cause allergies, inflammation, immunological abnormalities, imbalances in epidermal homeostasis, and other skin illnesses. Causes of skin aging include stress, lack of sleep, exposure to ultraviolet (UV) and undernourishment, omitting age‐induced natural aging and photoaging [178]. Wrinkle formation in the skin is primarily attributed to diminished cellular regeneration in the epidermal layers, reduced synthesis of structural proteins such as collagen and elastin, and a decline in extracellular matrix components within the dermis. Collagen and elastin together constitute over 90% of the dermal protein content and play a crucial role in maintaining skin elasticity and firmness. The enzymatic degradation of these proteins by collagenase and elastase significantly accelerates the aging process and the appearance of wrinkles. The antiaging properties of Triphala extracts are largely due to their potent antioxidant activity and their ability to inhibit these enzymes, thereby preserving dermal integrity and reducing wrinkle formation. Polyphenols and flavonoids neutralize free radicals or highly reactive molecules that damage cellular components, including collagen and elastin [179]. Tyrosinase is a key enzyme in melanin synthesis, and its inhibition reduces melanin production, leading to skin whitening. Triphala extracts showed significant tyrosinase inhibitory activity and anti‐wrinkle effect [180]. 5.9. Effect on the Ophthalmic System Triphala at the dose of 25 mg/kg, Triphala Ghrita, Triphaladi Gana Vati treated cataractogenesis, by increasing antioxidant enzymes in lens homogenate and preventing retinal damage [18, 87]. Aqueous extract of Triphala treated uveitis in rabbits [88]. Triphala Ghrita treats dry eye syndrome by preventing the release of T cells from cytokines and promoting lipid production. Dry eye syndrome is characterized by the sensation of burning, irritation, photophobia, mucus/film formation, blurring of vision, congestion and prickling pain due to strain, which is caused by tear film damage (change in lipid, water, and mucin content). In the prospective comparative clinical study of dry eye syndrome patients, treated with Triphala Ghrita tarpana (10–15 mL) for 7 consecutive days orally, a recovery was observed (73.3%) [89]. In patients with computer vision syndrome, Triphala eye drops (four times per day) relieve burning sensation, blurring vision, light and glare sensitivity and eye strain of about 48.8% [90]. A labelled RCT with 91 glaucoma patients was treated with oral administration of Chakshushya Rasayana (contains Triphala) along with β‐blockers (topical antiglaucoma drops) for a 3‐month duration, which improves retinal sensitivity up to 12dB [181]. Chebulagic and Chebulinic acid in Triphala also reduce peripheral vascular resistance in blood vessels. Administration of aqueous (30–300 µg/mL) and alcoholic extract (50–500 µg/mL) of Triphala in patients with proliferative vitreoretinopathy, that is, rhegmatous retinal detachment, reverses the decreased gene expression of Zonula occludens‐1, E‐cadherin and cytokeratin and expression of MMP‐2 and MMP‐9 in retinal pigment epithelial cells [164]. 5.10. Effect on Immune System 5.10.1. Antioxidant/Anti‐Inflammatory Studies In any disease, the primary attack on the physiological system is initiated by the release of ROS, preceded by the oxidation of proteins, lipids, and DNA in the cell. Then inflammation rises, which leads to inflammatory diseases like diabetes, cancer, atherosclerosis, neurodegenerative disease, and so forth. In organ damage, enzymes like glucuronidase, lysosome, and lactate dehydrogenase were released, and inflammatory mediators like TNF‐α synthesis, the release of COX‐2 enzyme were increased and accumulated. Triphala stabilizes the unstable free radical formations and prevents membrane damage in the physiological system due to its presence of antioxidant compounds like ellagic acid, ascorbic acid, punigluconin, gallic acid, isostrictiniin, corilagin, β‐sitosterol, and so forth [182]. 5.10.2. Anti‐Arthritis Arthritis is a joint inflammation characterized by oedema formation, joint pain, and stiffness. The oral administration of 1 g/kg of Triphala relieves inflammation of the synovium, reduces cartilage loss by attenuating the production of free radicals and membrane damage [183]. 5.10.3. Effect on the Microbial System Triphala acts as a broad‐spectrum anti‐pathogenic agent in combating antimicrobial resistance. Triphala significantly reduced the virulence of tested pathogens Chromobacterium violaceum, Serratia marcescens, S. aureus, S. pyogenes, and P. aeruginosa, leading to a 14%–41% improvement in the survival rates of infected worms Caenorhabditis elegans. This effect was reported pre‐ and post‐infection treatment (therapeutic prevention). Triphala modulated quorum sensing in certain multidrug‐resistant bacteria, suggesting a dual mechanism of action involving both growth inhibition and alteration of virulence factors [184]. Formulations like Triphala Mashi also possess antimicrobial properties [35]. The methanol, water, and ethanol extracts of Triphala were effective against strains like E. coli, E. faecalis, S. sonnei, A. hydrophila, Salmonella typhimurium, P. aeruginosa, S. flexneri, Salmonella paratyphi–B, Salmonella typhi, S. aureus, Klebsiella pneumoniae, Shigella sonnei, Vibrio cholerae, and Bacillus cereus. A similar effect was also observed in the blood samples obtained from HIV‐infected patients [113] 5.10.4. Radio‐Protective/Anti‐Mutagenic/Anticancer As an adjuvant, Triphala can be used in cancer treatment due to its potential properties, such as antioxidant, immunomodulant, anti‐inflammatory, and promoting gastrointestinal health. Triphala also mitigates the metastasis process [185]. Flavonoids, tannins, polyphenols, and some antioxidants present in the formulation protect from radiation and chemical‐induced mutagenicity. Anticancer drugs like bleomycin and paraquat cause DNA strand breakage by releasing free radicals, and ionizing radiation causes molecular lesions through both direct and indirect pathways. At the dose of 10 mg/kg, the radiation tolerance of Triphala was up to 1.4 Gy [186]. The aqueous extract (5–40 mg/kg) arrests intestinal and bone marrow damage [36, 187] by increasing the release of antioxidant enzymes and decreasing the release of xanthine oxidoreductase in the intestines [188]. Another study reported that oral administration of 1.5 g/kg/day for 10 consecutive days prevents acute intestinal mucosal damage induced by irradiation [189]. In patients with radiation therapy and people in the most proximity to nuclear plants, Triphala may be taken as a daily supplement since it protects from radiation injury. Triphala protects against irradiation from 7.5 Gy on 7 days of exposure, 12.5 Gy‐γ‐irradiation (single fraction) on 10 consecutive days and 10 Gy of 60Co gamma radiation at a dose rate of 1.33 Gy/min. Ionizing radiation directly damages macrophages by activating free radicals [187, 188, 189]. A report concluded that Triphala protects against gamma radiation‐induced lipid peroxidation [183]. The water, acetone, and chloroform extracts of Triphala show antimutagenic nature against TA98 and TA100 strains of S. typhimurium [190]. Lipoma is a soft tissue tumor, that is, the deposition of a cluster of fat cells under the skin, which appears as a solitary, soft, movable, and painless mass. They are often benign, large in size, and characterized by increased body weight and blood lipid profile. Triphala kala basti (therapeutic enema) modulated the condition to normal after its treatment for 15 days [105] due to the presence of polyphenols and flavonoids, which inhibit JNK and p38 pathways and activate ERK, PI3K/Akt, and PKC pathways in cells like neuronal, cardiac, endothelial, epithelial, hepatocytes, and macrophages. Such interactions of flavonoids with cell signaling pathways provide various beneficial effects in cancer therapy, such as improving brain function, preventing oxidative stress, preventing apoptosis, protecting against endothelial barrier dysfunction and injury [191]. In vitro and in vivo anticancer activities of Triphala are presented in Tables 3 and 4. TABLE 3. | Type of extract | Cell line | IC50 | Mechanism of action | Reference | |---|---|---|---|---| | Aqueous extract | MCF‐7(breast cancerP53 positive) | 13 ± 0.4 µg/mL at 24 h 10 ± 0.7 µg/mL at 48 h 8 ± 0.63 µg/mL at 72 h 4 ± 0.36 µg/mL at 120 h | p53 inhibition | [188] | | Aqueous extract | T47D (breast cancer p53 negative) | 26 ± 0.73 µg/mL at 72 h 23.9 ± 0.64 µg/mL at 120 h | No p53 inhibition | | | Aqueous extract | Capan‐2(pancreatic cancer) | 50 µg/mL | Increased activation of ERK and p53 has been observed in pancreatic tumor cells | [101] | | Aqueous extract | PANC‐1(pancreatic adenocarcinoma) | 115 ± 18 µg/mL | Suppressed the clonogenicity of HeLa cells Apoptotic cell death in cancer cells | [94] | | Aqueous extract | HeLa(cervical adenocarcinoma) | 98.28 ± 13.71 µg/mL | || | Aqueous extract | MDA‐MB‐231 (triple negative breast carcinoma) | 173 ± 20 µg/mL | || | Aqueous extract | MGC‐803 cells (gastric cancer) | 86.08 ± 3.87 µg/ml. | Regulation of the EGFR/Akt/ERK signaling cascade | [193] | | Aqueous extract | Hep G2 cells | 259.17 ± 7.04 at 48 h and 79.83 ± 3.16 at 72 h | To be studied | [194] | | Aqueous extract | Pancreatic cell line(BxPC‐3)Capan‐2 cells | Apoptosis induction by activating ERK | [101] | | | Aqueous extract | Barcl‐95 (mouse thymic lymphoma | 0.125 mg/mL | Decreases ROS generation via activation of apoptosis | [95] | | Aqueous extract | MCF‐10F (normal breast epithelial cells) | No cytotoxicity was observed | To be studied | | | Hydroalcoholic extract | Hep G2 (liver carcinoma) | 77.63 ± 4.3 µg/mL | To be studied | [98] | | Hydroalcoholic extract | SKOV‐3 (ovarian cancer) | 101.23 ± 7.76 µg/mL | To be studied | [146] | | Hydroalcoholic extract | HEC‐1B cells (endometrial cancer) | 95.56 ± 8.94 µg/mL | Decrease in the expression of phospho‐Akt, phosphor‐p44/42, and phosphor‐NF‐κB p56 and downregulation of MAPK/ERK, PI3K/Akt/mTOR and NF‐κB/p53 signaling pathways | | | Ethanol extract | LNCap (prostate cancer) | 63.6, 60, 48.1, and 33.3 µg/mL at 24, 48, 72, and 96 h | To be studied | [195] | | Methanol extract | N4X4 (brain cancer) | 15.31 mg/mL | To be studied | [193] | | Methanol extract | HCCSCs (human colon cancer stem cells) | 104 ± 5 µg/mL | Treatment suppressed c‐Myc and cyclin D1 expression, which shows that it acts in MAPK/ERK and Wnt/β‐catenin signaling pathways, with elevation of Bax/Bcl‐2 ratio in colon cancer stem cells | [97] | | Methanol extract | HCT116 (colon cancer) | 153 ± 8 µg/mL | Modulate inflammatory molecules through the upstream molecule, mucin Decreases the cell cycle regulators protein gene ratio c‐Myc/cyclin D1 and elevates the Bax/Bcl‐2 ratio to induce apoptosis Downregulates inflammatory cascade proteins like IL‐6, IFN‐γ, COX‐2, NF‐κB | | | Methanol extract | P388 (murine lymphocytic leukaemia) | 13.55 µg/mL | To be studied | [187] | | Acetone extract | S115PC3, MCF‐7 cell line (breast cancer) DU‐145 (prostate cancer) PC‐3 (prostate cancer) | At 80 µg/mL (25%–50% cell cytotoxicity) | To be studied | [192] | TABLE 4. | Dose | Cancer model | Observation | Reference | |---|---|---|---| | 2.5% of Triphala supplemented in diet | Benzo(a)pyrene [B(a)P] induced forestomach papilloma genesis in mice | 77.77% reduction in tumor incidence in short‐term study 66.66% in long‐term study | [196] | | Oral administration of 50 or 100 mg/kg Triphala in PBS, 5 days/week | Capan‐2 pancreatic tumor xenograft | Reduced tumor growth Increased apoptosis and activation of p53 and ERK | [101] | | Direct oral feeding of Triphala—40 mg/kg body weight | Barcl 95 xenograft model in mice | Reduces tumor growth and tumor volume in thymic lymphoma | [197] | | 5% Triphala on the diet for 2 weeks | Dimethylhydrazine dihydrochloride induced carcinogenic damage to the mouse liver | Decrease in the levels of SGPT, SGOT, and ALP followed by a decrease in precancerous lesions in the liver Inhibition of the ER stress signaling pathways ERp29 and ERp36 | [197, 198] | | Triphala | Gastric carcinoma in zebra fish | Regulation of the EGFR/Akt/ERK signaling cascade by inhibition of phosphorylation of genes | [199] | | Triphala 100 and 200 mg/kg | Transplantation of Hep G2 cells into the SCID mice to develop liver carcinoma | Dose‐dependent decrease in tumor weight and volume | [194] | | Triphala 60 mg/kg | Individuals exposed to gutkha and tobacco | Inhibition of precancerous oral mucosal lesions in oral cancer | [200] | 5.10.4.1. Mechanism of Action All these studies prove that the Triphala possesses components like gallic acid, ellagic acid, epigallocatechin gallate, chebulinic acid, chebulagic acid, and so forth, that exhibit its activity via Antioxidant compounds present in the Triphala induce apoptosis by regulating the intrinsic and extrinsic cell signaling pathways via activation of the p53 protein that induces the transcription of redox‐related genes that regulate ROS production, such as NOS 2, PIG 3, 6, and 12 and inactivation of cyclin‐D1 and c‐Myc oncogenes and inactivation of ERK [40] and thus Wnt pathway signaling to reduce proliferation and resistance [40, 97, 192]. It also acts as a key regulator of gene expressions of expression of phospho‐Akt, phosphor‐p44/42, and phosphor‐NF‐κB p56, and downregulation of MAPK/ERK, PI3K/Akt/mTOR, and NF‐κB/p53 signaling pathways [101]. Increases cytotoxic T cells and natural killer cells levels in humans by mediating the innate and humoral immune system [65]. It also prevents metastasis by suppressing cancer cell migration [92]. 5.10.4.2. Anti‐Angiogenesis It is the ability to reduce the unwanted growth of blood vessels (e.g., cancer). Triphala's constituents, which have anti‐angiogenic potential, are gallic acid, ellagic acid, and chebulinic acid [201]. The Triphala at the dose of 40 µg/mL inhibits VEGF and VEGF‐induced phosphorylation of VEGFR‐2, which stimulates PI3K/Akt/NF‐κB signaling pathway, aids in activating proliferation, migration, and tube formation between endothelial cells and promotes permeability in the neo‐vascularization process. Uni‐protein target therapies have resistance to anti‐VEGF therapy has been reported in tumor cells [201]. Hence, Triphala can be used as an adjuvant therapy due to its multi‐protein targeting nature in multiple pathways to inhibit angiogenesis. Punicalagin and chebulagic acid exhibited high binding affinities to multiple targets and revealed significant inhibition of angiogenesis in vitro. It also has a higher affinity with CD31, E‐selectin adhesion molecules in blood vessels, which inhibit cell migration and downregulate fetal growth factor in endothelial cells [202]. 5.10.5. Effect on Vector‐Borne Diseases Vector‐borne diseases are human illnesses caused by parasites, viruses, and bacteria. Many of these vectors are bloodsucking insects that ingest disease‐producing microorganisms during a blood meal from an infected host (human or animal) and later transmit it into a new host, after the pathogen has replicated. Often, once a vector becomes infectious, they are capable of transmitting the pathogen for the rest of its life during each subsequent bite. 5.10.5.1. Antimalarial Malaria is a parasitic infection transmitted by Anopheles mosquitoes. Triphala (600 mg/kg) acts against parasitaemia by decreasing the parasite load up to 75.7% in Plasmodium berghei. Ellagic acid and gallic acid have antimalarial properties. Gallic acid increases phagocytic activity in macrophages [203]. Triphala damages the intracellular proteins, lipids, and nucleic acids of the parasite and inhibits the biosynthesis of fatty acids during the intraerythrocytic cycle of Anopheles. The aqueous extract of Triphala exhibited good antimalarial activity [204]. 5.10.5.2. Treats Dengue Dengue is the most prevalent viral infection transmitted by Aedes mosquitoes. Triphala (100 µg) has inhibited the production of the Dengue virus from 3000‐ to 1000‐fold in Hu7 human cells and Vero cells. It also downregulated the expression of IL‐6, IFN‐γ‐induced protein 10, and CXCL‐10, which indicates a lowered risk of liver pathogenicity. Gallic acid interacts with NS5 and E proteins of the virus and inhibits the RNA synthesis and Nrf2‐antioxidative response element signaling pathway in both pre‐ and post‐treatment conditions due to its anti‐inflammatory and neutralizing capability of free radicals in oxidative stress [102]. 5.11. Protective Effects of Triphala The above (Figure 7) illustration reveals that Triphala's multi‐targeting nature protects all organs from damage by interacting with these genes: mTOR, Akt, TNFAIP1, LDH, COX‐1, COX‐2, LOX, MMP, TNF, MAPK, IL‐6, IL‐14, NF‐κB, PPARG, cEBBP, BAX, BCL‐2, TP53, P36, JNK, P38, ERK, cyclin D1, EGFR, ERK, PI3K, ERP29, ERP36. These genes were also involved in longevity regulation. Triphala regulates gut microbiota, boosts SCFA production, and modulates immune‐metabolic pathways to support treatment of chronic inflammatory diseases [205, 206]. Thus, they conserve their antiaging potential. FIGURE 7. Protective effects of Triphala. 6. Conclusion and Future Directions The multiple benefits of Triphala primarily stem from the fruits of T. chebula, T. bellirica, and E. officinalis, which are rich in polyphenols, flavonoids, tannins, and more. The therapeutic efficacy of Triphala in cancer treatment has been demonstrated, with the acetone extract exhibiting effectiveness against breast cancer and prostate cancer cell lines. However, the underlying mechanism of action has not been sufficiently investigated. Similarly, the therapeutic potential of hydroalcoholic extract against liver and ovarian cancer treatment remains inadequately explored. The mechanisms through which Triphala exerts its therapeutic properties in various protective and anti‐arthritic models have not been thoroughly elucidated. Furthermore, antiaging, anti‐neurodegenerative, and anti‐tuberculosis effects have to be explored widely. The multi‐protein targeting nature of Triphala Churna has shown decreased resistance, and promising therapeutic potential has been shown in various disease models. To gain a deeper understanding of its potential therapeutic benefits, comprehensive studies in proteomics, metabolomics, transcriptomics, and gut microbiomes are needed in different disease conditions with various vehicles (anupanas). Natural products and their phytochemicals present in the Triphala have important roles in the treatment of most ailments, and are also integral in the development of new synthetic compounds for therapeutic purposes. With the use of novel drug delivery and development technologies, targeted therapy can be achieved with Triphala in the future. Author Contributions Vinodkumar Thallada: conceived and designed the project, Editing, revision and Final corrections to the manuscript. N. Monika: drafted and made substantial improvements to the manuscript. T. Dinesh: drafted and made substantial improvements to the manuscript. G. Kusuma: drafted and made substantial improvements to the manuscript. Kousik Ghosh: reviewed the manuscript and provided a research‐oriented environment and various technical support. S. Chitra: reviewed the manuscript and provided a research‐oriented environment and various technical support. Conflicts of Interest The authors declare no conflicts of interest. Acknowledgments The authors express their sincere gratitude to the Director General, Central Council for Research in Ayurvedic Sciences (CCRAS), Ministry of Ayush, Government of India, for providing a research‐oriented environment and various technical support. Thallada V., Monika N., Dinesh T., Kusuma G., Ghosh K., and Chitra S., “The Multifaceted Benefits of Triphala: Uncovering Phytochemical and Pharmacological Properties From Antiquity to Modern Times.” Chemistry & Biodiversity 23, no. 1 (2026): e01825. 10.1002/cbdv.202501825 Funding: The authors received no specific funding for this work. Contributor Information Vinodkumar Thallada, Email: [email protected]. N. Monika, Email: [email protected]. Data Availability Statement All the data and materials provided in this manuscript were obtained from the included references.

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Data Availability Statement All the data and materials provided in this manuscript were obtained from the included references.