The Potential of Clerodendrum Plants as an Adjunct Therapeutic for Metabolic Syndrome

Abstract

Metabolic syndrome, characterized by an assemblage of metabolic abnormalities, including central obesity, insulin resistance (IR), high blood pressure, and dyslipidemia, constitutes a serious risk for the progression of cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM). Oral hypoglycemic drugs, such as biguanides and sulfonylureas, and cholesterol-lowering drugs, such as statins, are commonly prescribed. However, their long-term use may cause sleep disturbance, severe hypoglycemia, muscle pain, gastrointestinal issues, and lactic acidosis (rarely). Clerodendrum plants have gained increasing attention owing to their use in folkloric medicine and diverse pharmacological properties. These plants contain terpenes and terpenoids, flavonoids and flavonoid glycosides, phenylethanoid glycosides, steroids, steroid glycosides, anthraquinones, and cyclohexylethanoids, which have a cyclohexane ring linked to an ethyl group. This review aims to provide information on the potential of Clerodendrum plants as adjunct therapeutic candidates for metabolic syndrome. Articles were searched in PubMed and Scopus using the keyword “Clerodendrum”. Clerodendrum plants have the potential to lower blood glucose levels, improve glucose tolerance, normalize lipid profiles, activate endogenous antioxidant enzymes, prevent liver disorders in diabetic models, reduce proinflammatory cytokines, and decrease the risk of CVDs. Following the in vivo toxicity studies, these plants showed no significant adverse effects at the tested doses. However, owing to the limited number of articles reporting human studies, further investigations in clinical settings are required to confirm their efficacy and safety.

Introduction

Metabolic syndrome, characterized by an assemblage of metabolic abnormalities, including central obesity, insulin resistance (IR), high blood pressure, and dyslipidemia, constitutes a serious risk for the progression of cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM).1,2 These conditions have become a major global health concern as the incidence of T2DM and CVD continues to gradually rise,3 and shows considerable variation across individuals in terms of severity and clinical presentation. Alongside socioeconomic development and lifestyle shifts, the prevalence of metabolic-related diseases has increased markedly, posing serious threats to public health and quality of life.4 In addition, DM is a major and growing global health burden, with 588.7 million cases worldwide on 2024 and projections exceeding 852.5 million by 2050, while T2DM accounts for over 90% of all DM cases and the number of death caused by T2DM has raised from 10.4 million to 39.3 million since 1990 to 2021.5,6 The increasing rates of overweight and obesity worsen this trend, with over 2.6 billion adults classified as obese in 2020.7–10

Pharmacological treatments, such as biguanides (eg, metformin, a first-line drug that reduces blood glucose), sulfonylureas (drugs that block the ATP-sensitive potassium channel and directly induce insulin release from pancreatic β-cells), and statins (drugs that inhibit hydroxymethylglutaryl-CoA reductase, the primary rate-limiting enzyme that is responsible for synthesizing cholesterol), are commonly prescribed. However, their long-term use often causes adverse effects, including gastrointestinal discomforts, vitamin B₁₂ deficiency, hemolytic anemia, hyperlactatemia, and metabolic acidosis (metformin),11 severe, recurrent hypoglycemia, and weight gain (sulfonylureas),12,13 muscle pain, such as myalgia, myopathy, and rhabdomyolysis (statins).14 Therefore, identifying adjunct therapeutic candidates that are effective and safe for long-term use, particularly those derived from medicinal plants, remains an important priority in the management of metabolic syndrome.15

Medicinal plants continue to meet the growing demand for safer, more affordable, and accessible therapies. The use of plant-based remedies for disease management has been practiced for centuries and is commonly referred to as phytotherapy. Approximately 70−80% of the global population still relies on traditional medicine for treating illnesses, particularly in rural settings where access to modern healthcare services and technology may be limited.16–19 Traditional medicine is defined as the knowledge, skills, and practices based on theories, beliefs, and experiences indigenous to different cultures, used to maintain health and prevent, diagnose, improve, or treat physical and mental illness.18 In a cross-sectional survey among older adults in the USA from June 2005 to March 2006, 49% of the 3005 participants used a dietary nutritional supplement containing a plant or plant extract.19 Phytomedicines have been rooted in long-standing healing practices for both preventive and therapeutic purposes. Medicinal plants contain secondary metabolites, including aromatic substances such as phenolic compounds with antioxidant properties or their oxygen-substituted derivatives, namely tannins. Considering the vast diversity of plant species worldwide, numerous phytochemicals remain unidentified, and their biological activities have not yet been fully explored.18,20–22 Many plants have been studied for their pharmacological activities, including those in the genus Clerodendrum of the family Lamiaceae (previously placed in the family Verbenaceae).

The genus Clerodendrum, comprising approximately 237 species, is distributed predominantly in tropical and subtropical regions, as described in Plants of the World Online. In general, the morphology includes small trees, shrubs, woody vines, lianas, and sub-herbaceous perennials. The plants can be recognized by their long, tubular, showy flowers and enlarged reddish calyces, and by a four-lobed blue-purple fruit.23

Several Clerodendrum species are traditionally used as medicinal plants and, in certain regions, are also consumed as vegetables. For example, C. philippinum was described as the most frequently mentioned plant used to maintain blood glucose in an ethnobotanical survey in Gajapati district in India,24 and C. viscosum was used by the Marakh Sect of the Garo Tribe in Mymensingh District, Bangladesh, for the same purpose.25 The leaves were commonly crushed in water and taken daily before meals,24,25 and the leaf extract of C. viscosum was believed to exhibit antioxidant properties, along with blood sugar reduction.25

Phytochemical investigations have indicated that Clerodendrum plants contain hundreds of secondary metabolites that may be biologically active,26 making them a promising genus for the discovery and development of plant-based adjunct therapeutics. Earlier reviews have discussed the traditional uses and general pharmacological properties of Clerodendrum phytochemicals; however, a comprehensive synthesis integrating preclinical and clinical evidence across this genus in ameliorating metabolic syndrome remains limited. In this review, we highlight the potential of Clerodendrum plants as adjunct therapeutic candidates for metabolic syndrome by integrating ethnobotanical and pharmacological activity studies, including toxicity studies. The phytochemicals and their mechanisms of action are also discussed. Articles were searched in PubMed and Scopus using the keyword “Clerodendrum” without filters applied, with a publication period from 1996 to 2026, resulting in a total of 484 articles (summarized in Figures 1 and 2), whose trendline follows a polynomial equation, y = 0.0108x² − 42.494x + 41926, with an R² of 0.712. Among those, C. inerme, C. infortunatum, C. trichotomum, C. phlomidis, C. serratum, C. viscosum, C. volubile, and C. colebrookianum, respectively, are the most studied species during the time period. This U-shaped relationship between year (x-axis) and the number of published articles (y-axis) (Figure 2) shows an accelerating upward curve, meaning publication numbers grow faster over time, or the genus Clerodendrum is currently the focus of global interest. Articles were then screened for duplications using the web-based tool Rayyan.ai (https://rayyan.ai/), and those related to Clerodendrum plants for metabolic disorders were selected, including in silico, in vitro, and in vivo studies, published between 2015 and 2026. Additional articles describing phytochemicals, nutritional, in silico, and toxicity assays were searched for to comprehend the review.

Figure 1.

Pie chart of the number of articles studying the Clerodendrum plant species showing C. inerme, C. infortunatum, C. trichotomum, C. phlomidis, C. serratum, C. viscosum, C. volubile, and C. colebrookianum, respectively, as the most studied species during the time period.

Figure 2.

Scatter diagram showing the number of articles on Clerodendrum genus plants (y-axis) published from 1952 to 2026 (x-axis) whose trendline follows a polynomial equation, y = 0.0108x² − 42.494x + 41926, with an R² of 0.712. This U-shaped relationship shows an accelerating upward curve, meaning publication numbers grow faster over time, or the genus Clerodendrum is currently the focus of global interest.

Ethnobotanical Study

An ethnobotanical study identifies, disseminates, and documents the indigenous knowledge of plants to cure diseases in humans and livestock, and interrelates traditional healing practices with research-based pharmacology.27–29 Inevitably, there is an increasing tendency in the use of traditional and complementary medicine in many countries,27 among which is the genus Clerodendrum. The genus name originates from two Greek words: (1) kleros, meaning destiny or chance, and (2) dendron, meaning tree. The name Clerodendrum was created probably because some of the species were believed to have healing properties, while others were poisonous.30

Clerodendrum genus has been documented among hundreds of plants in several ethnobotanical surveys of traditional medicines across countries, such as those conducted in Northwest Yunnan, China,20 Gajapati district in India,24 in Mymensingh District, Bangladesh,25 in Sedie Muja, Ethiopia,27 in Limpopo, South Africa,31 in the Luhya community of Kakamega, Kenya,32 in the Mustang district in Nepal,33 and in Azad Jammu and Kashmir, in Pakistan.34 In those surveys, different species were mentioned, such as C. philippinum to reduce blood glucose,24 C. myricoides to treat swelling, anthrax, and evil spirits,27 C. ternatum to treat rhinitis,31 C. johnstonii to treat malaria,33 and C. viscosum for reducing blood glucose25 and fever,34, mostly using the leaves, barks, and roots, by crushing and squeezing them.

Botanical Aspects, Phytochemical, and Nutritional Composition

The name Clerodendrum was formally introduced by Carl Linnaeus (a Swedish biologist) in 1753 in his foundational publication, Species Plantarum, based on the species Clerodendrum infortunatum found in India.23,35 Clerodendrum was initially assigned to the Verbenaceae family,36 and subsequent taxonomic revisions, supported by morphological and molecular evidence, have reclassified the genus within the Lamiaceae family.23 In Thailand, a taxonomic synopsis recognized 26 Clerodendrum species, including 21 native species and seven introduced taxa, such as C. calamitosum L., C. minahassae Teijsm. and Binn., and C. quadriloculare (Blanco) Merr.35 In Western Australia, ten species of Clerodendrum have been recorded, thus further highlighting the broad geographic spread of the genus across major tropical regions.36 Two species of Clerodendrum plants important in Asia are C. colebrookianum Walp. (synonym C. glandulosum), popularly known as East India glory bower, and C. trichotomum Thunb., known as Harlequin glory bower.37 C. colebrookianum is indigenous to India, Malaysia, and Indonesia, where it is endemic.37 The other plant, C. trichotomum, is native to China, Korea, and Japan, but is commonly planted in gardens in Europe.38 This wide geographic distribution supports the extensive ethnomedicinal use of Clerodendrum plants.

Clerodendrum plants have been reported to contain 283 compounds successfully isolated and identified from different species, including monoterpenes and their derivatives, sesquiterpenes, diterpenoids, triterpenoids, flavonoids and flavonoid glycosides, phenylethanoid glycosides, steroids and steroid glycosides, cyclohexylethanoids, anthraquinones, and cyanogenic glycosides.26 Abietane diterpenoids have been isolated from the stem extract of C. kiangsiense, collected at the Wugong Mountain of Pingxiang City, Jiangxi, China.39 Abietanes are naturally occurring tricyclic diterpenoids commonly present in a variety of terrestrial plant sources.40 Two new abietane diterpenoids, along with five known diterpenoids, namely 6,12-dihydroxyabieta-5,8,11,13-teraen-7-one, 11,14-dihydroxy-8,11,13-abietatrien-7-one, clerodendrin A (C₃₁H₄₂O₁₂, PubChem CID 442013), cyrtophyllone A, and (10R,16S)-12,16-epoxy-11,14-dihydroxy-6-methoxy-17(15→16)-abeo-abieta-5,8,11,13-tetraen-3,7-dione are present in the stems of C. bracteatum collected at the Dulongjiang mountain, Yunnan, China.41 Another diterpenoid, clerodin (C₂₄H₃₄O₇, PubChem CID 442014), has been isolated from C. infortunatum leaves.42 The roots of C. glabrum contain diterpenoid compounds ferruginol (C₂₀H₃₀O, PubChem CID 442027) and royleanone (C₂₀H₂₈O₃, PubChem CID 442084), and β-amyrin palmitate, a triterpenoid compound.43 The leaves of C. infortunatum collected from Pabna, Bangladesh, contained three unidentified abietane-type diterpenoids and phenylpropanoids, such as jionoside C (C₂₉H₃₆O₁₃, PubChem CID 133561689), jionoside D (C₃₀H₃₈O₁₅, PubChem CID 9895632), brachynoside (C₃₁H₄₀O₁₅, PubChem CID 10032232), and incanoside C (C₃₆H₄₈O₂₀, PubChem CID 10010564).44 The roots of C. indicum from Phetchabun Province, Thailand, contain triterpenoids, such as 3β-hydroxy-D: B-friedo-olean-5-ene, oleanolic acid-3-acetate (C₃₂H₅₀O₄, PubChem CID 151202), taraxerol (C₃₀H₅₀O, PubChem CID 92097), lupeol (C₃₀H₅₀O, PubChem CID 259846), and 6 steroid glycoside compounds, isolated from the dichloromethane extract.45 Another type of glycoside, namely inerminoside E (C₃₁H₄₆O₁₆, PubChem CID 6443521), has been identified from C. trichotomum from Hefei city, Anhui province, China.46 Inerminoside E is one of the iridoid glycoside compounds, a group of terpenoid compounds found in at least 8 species of Clerodendrum plants.47 The protocatechuic acid, a phenolic acid compound that exhibits antidiabetic activity, has been isolated from C. volubile leaves extract obtained from Ifon, Ondo State, Nigeria.48 The phenolic compounds, clerodenoside A (C₃₅H₄₄O₁₇, PubChem CID 91884991), seguinoside K (C₁₇H₂₄O₁₁, PubChem CID 272787149), verbascoside (C₂₉H₃₆O₁₅, PubChem CID 5281800), and isoverbascoside (C₂₉H₃₆O₁₅, PubChem CID 6476333), have been characterized from C. inerme’s stem obtained from Thai Binh Province of Vietnam.49 The phenolic compound verbascoside, was also present in C. glandulosum leaves.50 Clerodendrum plants are known for their rich source of flavonoids with many biological activities.51,52 Pectolinaringenin flavonoid (C₁₇H₁₄O₆, PubChem CID 5320438) and andrographolide diterpenoid (C₂₀H₃₀O₅, PubChem CID 5318517) have been isolated from C. phlomidis leaves collected in Maharashtra, India. In addition, pectolinaringenin-7-O-β-D-glucopyranoside, together with three unidentified flavonoid glycosides, have also been identified.52 Pectolinaringenin is present in C. indicum together with hispidulin (C₁₆H₁₂O₆, PubChem CID 5281628),45 whereas apigenin 7-O-β-D-glucuronide, apigenin (C₁₅H₁₀O₅, PubChem CID 5280443), luteolin (C₁₅H₁₀O₆, PubChem CID 5280445), and quercetin (C₁₅H₁₀O₇, PubChem CID 5280343) are found in the leaves and roots of C. trichotomum.46

Furthermore, several edible Clerodendrum plants are used as vegetables due to their nutritional content,53,54 such as C. celebrookianum,53 C. glandulosum,54 and C. volubile, which contains protein and minerals, eg, sulfur, chlorine, manganese, iodine, and zinc, and vitamins, eg, vitamin A, C, B3, B6, and B12.55,56 Other species, namely C. indicum and C. glandulosum (synonym C. colebrookianum Walp), were also reported to contain protein, fiber, fat, ash, carbohydrate, and vitamin C.57,58

Pharmacology Activities Related to Metabolic Disorders

In silico Studies

In silico molecular docking is commonly used to simulate the interaction of small molecules with proteins or receptors to predict their biological activities. Eight articles reporting in silico studies related to metabolic disorders are included in this review.48,59–65 The target proteins used are those related to carbohydrate degradation or regulating carbohydrate metabolism and glucose homeostasis, such as α-glucosidase,48,60,63–65 α-amylase,60 aldose reductase,60 peroxisome proliferator-activated receptor-γ (PPAR-γ),61 and Rho-associated coiled-coil protein kinase I (ROCK I),59 and those related to the inflammatory pathway, such as tumor necrosis-α,48 human inducible nitric oxide synthase,61 ROCK I,59 ROCK II,59 phosphodiesterase 5,59 liver X receptor-β,61 liver X receptor-α,61 HMG-CoA reductase,61 protein kinase C-α (PRKCA),62 and protein kinase C-ζ (PRKCZ).62 These studies revealed that phenolics and flavonoids in Clerodendrum plants interact with various proteins involved in carbohydrate metabolism or glucose homeostasis and inflammation, suggesting their potential as hypoglycemic and/or anti-inflammatory agents.

α-Glucosidase and α-amylase inhibitors are well-suited for mitigating postprandial hyperglycemia, a common problem among T2DM patients. These competitive and reversible inhibitors interact with the enzymes in the brush border of the small intestine by hydrolyzing carbohydrates into monosaccharides.66 The active site residues are Trp59, Tyr62, Gln63, Thr163, Arg195, Asp197, Lys200, His201, Glu233, Glu240, and Asp300 for α-amylase,67 and Phe159, Phe178, Arg213, Val216, Glu277, Phe303, Arg315, Tyr316, Asn350, Asp352, Gln353, Glu411, and Arg442 for α-glucosidase.64,67

Two compounds of C. volubile, trimethoxykaempferol and biochanin, owing to their hydroxyl or carboxyl moieties, interact with the human maltase glucoamylase, the major class of α-glucosidase that is expressed in the small intestine, by building bonds with residues Asp203, Arg526, Asp443, Phe450, and His600 in the enzyme’s active site. This in silico study was validated by an in vitro study, indicating that the dichloromethane fraction of C. volubile significantly inhibited α-glucosidase comparable to acarbose, the standard α-glucosidase inhibitor.65

During the initial phase of starch digestion, salivary α-amylase converts dietary polysaccharides into simpler oligosaccharides by cleaving their α-1,4-glucan linkages, which are eventually degraded by the intestinal α-glucosidase.68 In previous molecular docking studies, protocatechuic acid, a phenolic compound of C. volubile, builds hydrogen bonds with essential residues in the active site of α-glucosidase.48,64 The molecular docking study was validated in a diabetic animal model, revealing that the ethyl acetate fraction of C. volubile leaf significantly lowered blood glucose and hepatic biomarkers, increased serum insulin and β–cell function, and protocatechuic acid isolated from this fraction markedly reduced phagocytic oxidative burst.48

Four phenolic compounds of C. glandulosum, namely verbacoside, isoverbacoside, apigenin, and caffeic acid, exhibited strong and stable interactions with α-glucosidase, α-amylase, and aldose reductase by building hydrogen bonds with important residues. These results were validated in an in vitro enzyme-inhibitory assay and in vivo streptozotocin-nicotinamide-induced diabetic rats.60 Phenylethanoid glycosides in C. glandulosum have the potential to treat diabetic wounds, as reported in a study integrating network pharmacology, molecular docking to PRKCA and PRKCZ, and molecular dynamics simulation.62 Furthermore, PPAR-γ agonists, which are highly expressed in adipocytes and stimulate their differentiation, have the main mechanism of the insulin-sensitizing action by reducing lipid supply to the muscle and liver.69 The key residues of PPAR-γ are Ser289 and Lys367.70

In vitro Studies

Numerous in vitro studies have described the antidiabetic and anti-inflammatory effects of Clerodendrum plants.50,55,61,63,71–77 Inhibition of α-glucosidase has been reported in C. glandulosum,50,60,72 C. squamatum,63 C. glabrum,71 C. phlomidis,73 C. splendens,74 and C. volubile.55,75–77 C. glandulosum is the most studied species. In one study, pretreatment with this plant extract markedly reduced ROS, DNA damage, and lactate dehydrogenase in palmitate-induced HepG2 cells, confirming its effects on ameliorating oxidative stress and mitochondrial dysfunction by upregulating the PGC1α/TFAM pathway.72 In addition, Clerodendrum plants also inhibit the pancreatic lipase enzyme.65 More interestingly, the formulation of C. glabrum water extract with silver nanoparticle preparation (Ag-NPs) showed no significant alteration in its biological activities, as it still shows inhibition against α-amylase, α-glucosidase, and hyaluronidase, suggesting its potential antidiabetic and anti-inflammatory properties.71 Inhibition of these enzymes, which may be attributed to phenolics and flavonoids, is a key therapeutic strategy in managing T2DM by regulating blood glucose levels and mitigating complications.78 Aldose reductase is the first enzyme involved in the polyol pathway and contributes to the pathogenesis of diabetic retinopathy. A hyperglycemic condition in patients with chronic DM often leads to excessive activity of this enzyme, resulting in the conversion of glucose to sorbitol within retinal cells, which depletes NADH and activates the formation of advanced glycation end (AGE) products.79,80 Metabolic disorders may manifest in the cardiovascular system as atherosclerosis, due to lipid accumulation, fibrous elements, endothelial dysfunction, and alteration of the immune pathway.81 In addition, by inhibiting hyaluronidase activity in diabetic conditions, the degradation of hyaluronic acid (an endogenous complex molecule contributing to cellular differentiation, inflammatory regulation, wound healing, and viscoelastic properties) is lessened, resulting in a more stable extracellular matrix and mitigating inflammation.82 Inhibition of hyaluronidase (Hyal1 and Hyal2) in diabetic conditions is a promising therapeutic strategy to prevent vascular complications by preserving the endothelial glycocalyx, a protective layer degraded by hyaluronidase activity during hyperglycemia.83

In vivo Studies

The in vivo antidiabetic activities of Clerodendrum plants have been reported for C. fragrans,84 C. glandulosum,60,85 C. infortunatum,86–89 C. phlomidis,90 C. splendens,88,91 C. squamatum,63 C. trichotomum,92 and C. volubile.48,65,66,93 Antidiabetic activity of these Clerodendrum plants was evaluated in concomitance with their anti-dyslipidemia60,90–93 and amelioration of liver function by decreasing AST, ALT, and ALP levels.84,85,91–93 In these studies, animals used were male Wistar rats,60,63,65,84,87,89–91,93 long-Evans rats,86,88 Sprague-Dawley rats,92 and C57BL/6 mice.85 Several inducers were used to obtain a diabetic condition, such as alloxan,84,90 streptozotocin,60,86,87,89 high-fat feed,62,88 and high-fructose feed.92 Doses used were various, ranging from 50 mg/kg body weight,93,100 mg/kg for 14 days,60,84,200 mg/kg for 14 days,60,250 mg/kg body for 18 days,86,88,400 mg/kg without describing the duration of treatment,89,90,500 mg/kg for 18 days,87,500 mg/kg for 16 weeks,92 1000 mg/kg for 18 days,87 and 1250 mg/kg for 28 days.86

Toxicity Studies

Acute and 28-day sub-chronic toxicity studies of several Clerodendrum plants, namely C. capitatum, C. glandulosum, C. polycephalum, C. thomsoniae, and C. umbelatum, have been conducted in different rodent species (mice, BALB/c mice, and Wistar rats) and different gender, through which have confirmed their safety. The detailed are described as follows:

The safety of C. capitatum leaf extract was investigated in an acute toxicity study in female Wistar rats at a single oral dose of 5000 mg/kg. This study described that the LD₅₀ value was higher than 5000 mg/kg.94 In the same article, a 28-day sub-chronic toxicity study was conducted in male and female Wistar rats, given doses of 4000, 8000, and 16,000 mg/kg/day, resulted in no significant changes in weight gain and food consumption, but there was an increase in leucocytes and hemoglobin, and a significant decrease in blood urea, hepatic enzymes, total cholesterol, and glucose.94

The safety of C. glandulosum leaf extract was investigated in an acute toxicity study in female Wistar rats at a single oral dose of 2000 mg/kg. This study resulted in no mortality or signs of toxicity in the first 4 h and 14 days observation, suggesting that the LD₅₀ value was higher than 2000 mg/kg.60

The safety of C. polycephalum leaf extract was investigated in an acute toxicity study in male adult mice at single oral doses of 1000, 2000, and 5000 mg/kg. This study resulted in no signs of toxicity or mortality at 2 h, 24 h, and 7 days.95 In the same article, a 28-day sub-chronic toxicity study was conducted in adult male rats given oral doses of 100, 200, and 400 mg/kg, resulted in no significant changes in body weight, hepatic enzymes, antioxidant enzymes (GSH, SOD and MDA), albumin, bilirubin, urea, creatinine, cholesterol, and HDL-cholesterol. Unexpectedly, a minor degree of vascular compression of the kidney in rats receiving 200 mg/kg and inflammatory infiltration in the liver and kidney in rats receiving 400 mg/kg were observed.95

The safety of C. thomsoniae leaf extract was investigated in two acute toxicity studies in male and female mice,96 and in only female mice.97 The first study described that the LD₅₀ was greater than 9000 mg/kg.96 In the same article, a 28-day sub-chronic toxicity study was conducted in adult male Wistar rats given oral doses of 312.5, 625, and 1250 mg/kg, resulting in no significant change in serum total cholesterol, hepatic enzymes (ALT and AST), and kidney function (creatinine), indicating no toxic effects.96 In addition, the safety of the ethyl acetate extract of the aerial part of C. thomsoniae in female mice and rats at single oral doses of 175, 500, and 2000 mg/kg has also been confirmed. The study suggested an LD₅₀ of greater than 2000 mg/kg. Similarly, a 28-day toxicity study conducted in both male and female Wistar rats revealed no significant changes in body weight, food intake, and hematological (hemoglobin, total erythrocytes, leucocytes, and thrombocytes), and biochemical analysis (SGPT, SGPT, ALP, urea, and creatinine).97

The safety of C. umbelatum leaf extract was investigated in an acute toxicity study in female BALB/c mice receiving a single oral dose of 2000 mg/kg. This study resulted in no significant changes or mortality over 14 days, thus the LD₅₀ value was greater than 2000 mg/kg.98 In the same article, a sub-chronic toxicity study was conducted in male and female BALB/c mice given oral doses of 200, 400, and 800 mg/kg for 28 days, resulted in significantly reduced water intake in male mice and increased water intake in female mice. Body weight of the female mice decreased, but there was no significant change in relative organ weights. No significant changes in hematological parameters were observed. There was a significant increase in ALT and AST levels in female animals receiving a dose of 400 mg/kg, and an increase in lipid profiles in female mice receiving a dose of 800 mg/kg; meanwhile, the same dose increased creatinine levels in males. Liver toxicity was observed in male mice receiving a dose of 400 mg/kg, and renal toxicity was observed in males receiving a dose of 800 mg/kg. The no-observed-adverse-effect level (NOAEL) of C. umbelatum aqueous extract was 200 mg/kg/day.98

Formulation of Clerodendrum Plants as a Supplement

Clerodendrum extracts have been formulated as supplements for treating diabetic conditions, as reported in two papers. In the first paper, C. serratum bark extract powder combined with Aegle marmelos leaf extract, Costus igneus leaf extract, Withania coagulans fruit extract, lactose, tragacanth, microcrystalline cellulose, fructose, magnesium stearate, clove powder, and Aswagandha powder underwent direct compression to produce chewable tablets intended as a supplement for diabetic conditions. The chewable tablet exhibited good flow properties, was black in color, with an aromatic odor, and a bittersweet taste.99 The second paper reported C. volubile as a health supplement in the form of a soup powder which contained high fiber and carbohydrate levels.100

Published Case Reports of the Effects of Clerodendrum Plants

Four articles reported the efficacious effects of Clerodendrum plants, particularly C. serratum and C. phlomidis, either alone or in combination with other plants. Nevertheless, only one of the cases was related to metabolic syndrome (the fourth case). The details are as follows:

In the first case, a 63-year-old female with a non-healing ulcer on the dorsum of the right foot after a snakebite was admitted to a clinic and treated with a 15 mL oral liquid containing C. serratum mixed with Rubia cordifolia, Cyperus rotundus, Pongamia pinnata, Zingiber officinalis, Saussurea lappa, Curcuma longa, Berberis aristata, Terminalia chebula, Terminalia bellerica, and Emblica officinalis, twice a day after a meal for 9 days. The patient showed improvement in ulcer healing, swelling, and pain. In this case, no adverse events were reported.101

The second case reported a male patient, aged 50 years, who had bronchial asthma for 15 years with hypertension. He received a three-gram powder containing equal weight of C. serratum and Z. officinale for 3 months. Asthma symptoms were evaluated monthly after the treatment, which revealed a 70% reduction in symptoms, and at the end of treatment, the asthmatic attacks ceased. It was explained that phytochemical compounds contained in C. serratum, such as phenolic glycoside, hispidulin, scutellarein, saponin, steroidal glycosides, and ferulic acid, may contribute to its bronchodilator and anti-inflammatory effects.102

The effectiveness of C. serratum in mitigating asthma was also reported in the third case of a 56-year-old male who complained of having an asthmatic cough and wheezing intermittently for 26 years. The patient was treated with two herbal combinations for 17 days. On days 1 to 3, the patient consumed a combination of Acalypha indica leaf juice (50 g in 100 mL water) and continued with a decoction containing the whole plant of C. serratum (30 g) and fresh rhizome of Z. officinalis (30 g). The symptoms of asthma and duration of attacks were completely relieved after completing the treatment. The antiasthma activity of the combination of C. serratum and Z. officinalis was thought to be attributed to its anti-inflammatory, antiallergic, and antihistaminic activities.103

Another species, C. phlomidis, was reported in the fourth case of a 60-year-old female with diabetes for 5 years with poor control. The patient had pain and restricted abduction, adduction, external rotation, and flexion on the right shoulder for two months. She received an Ayurvedic herb called Vathakesari thylam, containing a mixture of C. phlomidis, Euphorbia antiquorum, Vitex negundo, goat’s milk, Calotropis gigantea, gingelly oil, castor oil, Terminalia chebula, Allium sativum, Ferula asafetida, sulphur, Costus speciosus, Z. officinale, Piper attenuatum, P. nigrum, P. longum, and Brassica juncea in 10 g amounts, respectively. The herb was administered once daily for 15 days in the hospital and continued for six months post-discharge, resulting in reduced pain and improved movements. No adverse events were observed during the treatment.104

Human Studies of Clerodendrum Plants in Metabolic Syndrome

Studies of Clerodendrum plants in humans are reported in two articles as follows:

C. infortunatum was evaluated for its effects on blood glucose when used as a chew stick in 27 healthy individuals. The participants were asked to chew one end of the twig, brush their teeth with the chewed end, and swallow the saliva. Blood glucose was evaluated before and after treatment with a chew stick. The decrease in blood glucose level ranged from 3 mg/dL to 59 mg/dL.105

C. phlomidis has been observed in 66 patients with obesity, but only 53 patients completed the study. In this study, C. phlomidis juice was combined with an Ayurvedic medicine, dried, and filled into capsules at a dose of 500 mg each. Each patient received two capsules twice daily for 10 weeks. Supplementation with C. phlomidis significantly decreased BMI, skin fold thickness, postprandial blood glucose, total cholesterol, LDL-cholesterol, and triglycerides, and increased HDL-cholesterol, but those were not statistically significant.106

Mechanism of Action of Bioactive Compounds in Ameliorating Metabolic Syndrome

Several mechanisms have been proposed in the pathogenesis of metabolic syndrome, including insulin resistance, dysregulation of lipid metabolism, obesity, and inflammation.107 The phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway is involved in metabolic disorders and plays a role in metabolism, cell proliferation, and cell survival. Hyperactivation of mTOR induced by proinflammatory cytokines and a hypercaloric diet can promote insulin resistance,108 eventually causing dysregulation of glucose uptake and mediating lipolysis in the liver, increasing free fatty acids (FFA). FFA can affect insulin receptors in muscles associated with PI3K/AKT activity, promote a decrease in GLUT-4 translocation, and reduce glucose uptake. Another study found that the AMPK pathway contributes to insulin resistance and dyslipidemia. AMPK pathway has many roles in metabolism, and its pathway can interact with the PI3K/AKT pathway, peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1), NADPH oxidase 4 (NOX4), and nuclear factor-kappaB (NF-κB).109 Several flavonoid compounds identified and isolated in the Clerodendrum plants, such as quercetin and apigenin, can interfere with the pathway involved in the pathogenesis of metabolic syndrome. The possible mechanism of phytochemicals of Clerodendrum plants in interfere glucose and lipid metabolism pathways is illustrated in Figure 3. Quercetin enhances tyrosine phosphorylation in the insulin signaling pathway and affects lipid metabolism by downregulating the expression of sterol regulatory element-binding protein (SREBP)-1c and fatty acid synthase.110 Flavonoid compound, apigenin, which has been isolated from C. trichotomum, improved the expression of insulin receptor, IRS-1, PI3K, AKT, and GLUT4 in the 3T3-L1 adipocyte cell line. Moreover, PI3K, AKT, and GLUT4 levels increased, and glucose uptake was stimulated.111 In vivo study confirmed that apigenin downregulated the expression of genes related to lipolysis and lipogenesis in the liver, such as lipoprotein lipase (LPL), PPAR-γ, SREBF1, diacylglycerol O-acyltransferase 2 (DGAT2), and stearoyl-CoA desaturase 1 (SCD1). The level of the inflammatory cytokine, TNFα, was reduced in animals treated with apigenin.112 Verbascoside or acteoside, a phenylethanoid compound, which has been identified in Clerodendrum plants, showed ameliorative effects on lipid metabolism, which reduced lipid deposition in the liver by regulating cardiolipin, ether-linked phosphatidylcholine, lysophosphatidylcholine, phosphatidylcholine, oxidized phosphatidylcholine, oxidized phosphatidylethanolamine, triacylglycerol, and sphingomyelin, thus reducing atherosclerosis risk.113 Verbascoside suppresses the AMPK and mTOR expression in the aortic tissue of an atherosclerotic animal model, which eventually decreases cardiovascular risk.114 Abietane diterpenoids increased AMPK activation as an energy sensor and upregulated the level of GLUT4. It also activates PPAR receptors, such as PPAR-γ, which plays a role in homeostasis of lipid and glucose metabolism.115 Abietane diterpenoid contained in C. trichotomum116 modulated lipid metabolism by decreasing the expression of SREBP-1, FAS, and SCD. In addition, it increased AMPK phosphorylation and PPARα expression in animals with dyslipidemia. The KEGG pathway analysis showed that C. trichotomum supplementation mainly affected the PPAR and PI3K-Akt pathways.92 Terpenoids have a wide pharmacological role, including ameliorating NAFDL by intervening in several pathways and receptors, including the AMPK, PPARs, Nrf-2, and SIRT1.117 Triterpenes compounds, such as oleanolic acid derivatives identified in C. indicum, can suppress the promoter activities of the Liver X receptor response element and SREBP-1c, resulting in decreased hepatocellular lipid content.118

Figure 3.

Mechanisms of Clerodendrum plants’ phytochemicals targeting glucose and lipid metabolism pathways to ameliorate metabolic disorders. Black arrows indicate direct pathways and red lines indicate inhibition. This figure was created using Canva (https://www.canva.com/).

Limitations of the Study

Although this review provides the phytochemical and pharmacological aspects of Clerodendrum plants in ameliorating metabolic syndrome, several limitations that could affect the interpretation of the results must be acknowledged. For example, (1) the heterogeneity of the extraction solvents (water, ethanol, ethyl acetate) and plant parts (leaves, bark, root) may affect the results; (2) in vitro studies investigated the pancreatic lipase, α-amylase, α-glucosidase, and hyaluronidase, while in vivo models used different inducers to obtain a diabetic condition (alloxan, streptozotocin, high-fat feed, and high-fructose feed), and different rodent types (Wistar rats, long-Evans rats, Sprague-Dawley rats, and C57BL/6 mice). This could be a discrepancy between in vitro and in vivo models that remains a concern; (3) data on pharmacokinetics and bioavailability of Clerodendrum extracts (or their metabolites) in animals and humans are limited; consequently, the evidence-based findings are not fully translated to humans; (4) only a few articles reported human studies on Clerodendrum, mostly in the form of cases, thus limitations of the study are heterogeneity in clinical presentation and only one clinical study related to metabolic disorder disease. The lack of clinical studies with adequate methods in patients with metabolic disorders needs further studies.

Conclusion

Clerodendrum plants and their bioactive secondary metabolites continue to be the global focus of interest, as proven by a total of 484 articles published between 1996 and 2026. These plants contain terpenes and terpenoids, flavonoids, flavonoid glycosides, phenylethanoid glycosides, steroids, steroid glycosides, anthraquinones, and others. In silico studies have shown that the metabolites interact with proteins related to carbohydrate degradation or regulation of carbohydrate metabolism and glucose homeostasis, such as α-glucosidase, α-amylase, aldose reductase, PPAR-γ, and ROCK I, and those related to the inflammatory pathway, such as tumor necrosis-α, human iNOS, ROCK I, ROCK II, phosphodiesterase 5, liver X receptors, HMG-CoA reductase, PRKCA, and PRKCZ. In vitro studies have demonstrated the antidiabetic and anti-inflammatory effects of Clerodendrum plants. Inhibition of α-glucosidase has been reported in C. glandulosum, C. squamatum, C. glabrum, C. phlomidis, C. splendens, and C. volubile, with C. glandulosum being the most studied species in vitro. The in vivo hypoglycemic activities in concomitance with the antidyslipidemia and hepatoprotective activities of Clerodendrum plants have been reported for C. fragrans, C. glandulosum, C. infortunatum, C. phlomidis, C. splendens, C. squamatum, C. trichotomum, and C. volubile, with C. volubile being the most studied species. Intriguingly, only C. phlomidis and C. infortunatum have been studied in humans, demonstrating their potential as adjuvant therapies in metabolic syndrome. There are four case reports on the efficacious effects of Clerodendrum plants, particularly C. serratum and C. phlomidis, but only one article related to metabolic syndrome, while the other cases described the effectiveness of the plants in mitigating asthma symptoms and attacks, thus highlighting the heterogeneity of clinical presentations. However, due to the limited number of clinical studies employing adequate methodologies to evaluate the efficacy and safety of these plants in the management of metabolic syndrome, further studies are still required to ensure evidence-based therapy.

Funding Statement

The Indonesian Endowment Fund for Education (LPDP), on behalf of the Indonesian Ministry of Higher Education, Science and Technology, and managed under the EQUITY Program (document contract number 4303/B3/DT.03.08/2025 and 3927/UN6. RKT/HK.07.00/2025) for the APC.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declared that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.