Phytochemical insights and pharmacological advances of Lepidium sativum L. (garden cress): bridging traditional medicine and evidence-based therapeutics

Abstract

Background

Lepidium sativum L. is a medicinal plant in the Brassicaceae family that has been used for the production of food and medicine. Scientists are becoming interested in it because of its rich phytochemical profile and ethnomedical uses. Nonetheless, a comprehensive understanding of its conventional use, bioactive components, pharmacological actions, and therapeutic significance is still crucial.

Objective

This review examines Lepidium sativum's traditional uses, phytochemical profile, pharmacological actions, and toxicological and safety considerations.

Methods

A literature search was conducted via PubMed, Scopus, Web of Science, and Google Scholar. This review was conducted in accordance with SANRA, and the findings were synthesized qualitatively.

Results

This review shows Lepidium sativum has a variety of pharmacological activities, including anti-inflammatory, analgesic, antimicrobial, antidiabetic, gastroprotective, hepatoprotective, nephroprotective, cardioprotective, neuroprotective, osteoprotective, wound-healing, reproductive, and anticancer effects. Bioactive components such as glucosinolates, alkaloids, phenolics, flavonoids, coumarins, and lignans are mostly responsible for these activities. These compounds affect cellular signaling, oxidative stress, inflammation, apoptosis, and metabolic pathways. Nevertheless, differences in phytochemical content, extraction techniques, dosage, bioavailability, and lack of standardization limit clinical translation. Traditional dosages of Lepidium sativum are usually harmless, but excessive doses or extended exposure to concentrated formulations may be harmful.

Conclusion

Lepidium sativum is a promising multipurpose medicinal plant that combines traditional knowledge with contemporary pharmacological research. Phytochemical bioactives and biological effects enable its growth as a source of functional foods, nutraceuticals, and medicinal agents. To determine its therapeutic potential, more research on molecular pathways, safety assessment, and clinical validation is necessary.

1. Introduction

Lepidium sativum L., or Garden cress, is a member of the Brassicaceae family and a significant medicinal and nutritional plant that has attracted increasing scientific attention due to its broad pharmacological potential, diverse phytochemical composition, and numerous ethnomedicinal uses.¹ It has been utilized as a food ingredient and a traditional cure in many parts of the world, including Asia, Africa, Europe, and the Middle East.² Many parts of Lepidium sativum, especially the seeds, leaves, and aerial parts, have been used for centuries in traditional healthcare systems for their medicinal and nutritional properties.³ Garden cress seeds are frequently used as expectorants, carminatives, laxatives, diuretics, and galactagogues; historically, they have been considered a tonic.² Additionally, they have been used to treat gastrointestinal disorders such as constipation, indigestion, and abdominal pain; respiratory disorders such as cough, bronchitis, and asthma-like symptoms; inflammatory conditions; fever; pain; anemia; metabolic disturbances; and delayed wound healing.4, 5 The plant has been used to aid breastfeeding, improve nutritional status, and boost general health. The mucilaginous properties of the seeds support their traditional usage as a calming and protective agent for gastrointestinal discomfort.⁶

Lepidium sativum's complex phytochemical profile is largely responsible for its medicinal potential.⁷ Many bioactive compounds, including flavonoids, phenolic compounds, alkaloids, glucosinolates, isothiocyanates, terpenoids, volatile compounds, fatty acids, proteins, amino acids, polysaccharides, vitamins, minerals, tannins, saponins, steroids, and glycosides, have been found through phytochemical studies.⁸ Brassicaceae plants are characterized by glucosinolates and their enzymatic breakdown products, particularly isothiocyanates, which support cellular defense, antibacterial, chemoprotective, and antioxidant properties.⁹ The nutritional and pharmacological relevance of Lepidium sativum is further enhanced by the inclusion of fatty acids, such as α-linolenic acid, linoleic acid, and oleic acid, as well as proteins, amino acids, mucilaginous polysaccharides, vitamins, and minerals.¹⁰

Lepidium sativum's various phytoconstituents contribute to its broad range of pharmacological effects through cooperative interactions with several biological targets and signaling pathways. A few of the many pharmacological activities that Lepidium sativum exhibits are antioxidant, anti-inflammatory, antibacterial, metabolic, protective, analgesic, wound-healing, immunomodulatory, neuroprotective, and reproductive health-promoting activity.¹¹ Some of the mechanisms that mediate these effects are reduction of oxidative stress, suppression of inflammatory mediators, immune response regulation, improvement of glucose and lipid metabolism, enhancement of antioxidant defense systems, protection of critical organs, and preservation of cellular homeostasis.⁷

Despite Lepidium sativum's traditional use, more recent developments in phytochemistry, molecular pharmacology, and biomedical research have shed light on the plant's medicinal potential.⁶ Its potential as a source of functional foods, nutraceuticals, and plant-derived therapeutic agents is highlighted by nutritional components and bioactive secondary metabolites, which provide scientific support for its ethnomedical applications.¹² Additionally, Lepidium sativum reduces oxidative stress, inflammation, microbial growth, metabolic imbalance, and tissue damage, offering prospects for the identification of multifunctional natural products.⁶ Therefore, to determine its therapeutic efficacy and support the logical development of new plant-based therapies, a thorough examination of its phytochemical composition, molecular mechanisms, pharmacological activities, safety features, and clinical significance is necessary.

2. Materials and methods

2.1. Review design and methodological framework

This narrative review synthesized the phytochemical profile, pharmacological activities, molecular mechanisms, safety profile, and therapeutic potential of Lepidium sativum. To increase methodological transparency, scientific rigor, and repeatability, the review process was created and reported in accordance with the criteria of the Scale for the Assessment of Narrative Review Articles (SANRA).¹³

2.2. Literature search strategy

A thorough literature search was conducted via electronic databases such as PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. To find pertinent papers about Lepidium sativum, a search was conducted from 2000 to 2026. “Lepidium sativum”, “garden cress”, “traditional medicine”, “ethnopharmacology”, “phytochemistry”, “phytochemical constituents”, “bioactive compounds”, “glucosinolates”, “flavonoids”, “phenolic compounds”, “pharmacological activities”, “molecular mechanisms”, and “therapeutic potential” were among the search terms that were created based on the review's objectives. The search results were optimized and refined using Boolean operators (AND, OR).

2.3. Eligibility criteria

Publications were chosen based on how well they addressed the review's goals. Peer-reviewed original research articles, review articles, and other scientifically significant publications outlining Lepidium sativum's traditional value, phytochemical profile, pharmacological activity, mechanisms of action, and safety features were all considered eligible sources. Regardless of the study paradigm, publications that offered significant evidence of the plant's medicinal potential were included. Studies without Lepidium sativum, duplicate records, inaccessible full-text articles, non-scientific reports, or publications with insufficient details about the phytochemistry, biological activities, or medicinal significance of the plant were all excluded.

2.4. Data extraction and organization

In accordance with predetermined theme areas, such as traditional value, phytochemical constituents, pharmacological activities, molecular targets and signaling pathways, and toxicological considerations, pertinent data were separately extracted and arranged.

2.5. Evidence synthesis

A narrative technique was used to synthesize the gathered evidence qualitatively. The findings were critically analyzed by combining data from phytochemical analyses, pharmacological research, and ethnobotanical studies. The chemical structures were searched from PubChem (https://pubchem.ncbi.nlm.nih.gov/substance/481107917).

2.6. Quality assurance and limitations

Based on study design, scientific validity, consistency of findings, and contribution to the review's goals, the methodological quality and applicability of the collected literature were critically examined. Since this study was a narrative review rather than a quantitative data pooling or meta-analysis, the results were interpreted with heterogeneity among studies, variations in extraction techniques, plant parts, geographical origins, and experimental models.

3. Traditional and ethnomedicinal uses of Lepidium sativum

Lepidium sativum L. has long been used traditionally in many cultures, especially in Ayurvedic, Unani, and folk medicinal systems. Several plant parts, particularly seeds, leaves, and aerial parts, have been used to treat a variety of medical ailments because of their nutritional and bioactive compounds.11, 12 Traditionally, Lepidium sativum seeds have been used as a carminative, appetite stimulant, and digestive aid to alleviate gastrointestinal pain, such as indigestion, constipation, and flatulence.³ Soaked seeds are traditionally taken for cough, sore throat, bronchitis, and other respiratory issues because of their mucilaginous qualities, which also make them a popular demulcent to relieve irritated mucous membranes.¹⁰ Lepidium sativum seeds are used in traditional medicine to increase mucus clearance and reduce symptoms related to asthma and respiratory congestion, due to their warming and expectorant properties.¹⁰ According to Vazifeh et al.,⁷ the plant's anti-inflammatory properties have been used for inflammatory diseases.

Lepidium sativum has long been used in women's health, especially to encourage uterine contractions after childbirth and support lactation.³ In some traditional cultures, seeds are taken as a nutritional supplement and galactagogue during the postpartum phase.³ Additionally, the leaves and seeds are used to treat skin disorders and wounds. Plant medicines are traditionally used to treat mild infections, promote wound healing, and lower skin irritation.10, 14 Its value in traditional treatments for microbial diseases has been supported by its antibacterial properties.¹⁴ Additionally, Lepidium sativum has long been used to treat lipid imbalance and hyperglycemia, among other metabolic problems.⁶ It is a dietary supplement used to boost immunity, improve general health, and give nutritional support because it contains proteins, minerals, vitamins, fatty acids, and phytochemicals.¹² Lepidium sativum is used as a tonic to boost general vitality, treat fever, and relieve pain in various traditional systems.³ In some cultures, the seeds are also administered topically to relieve muscle and joint pain.¹⁵ The major morphological parts of Lepidium sativum L. traditionally used for medicinal purposes are shown in Fig. 1.

Fig. 1.

Morphological characteristics of Lepidium sativum L. showing the (A) flowers, (B) pods (fruits), (C) seeds, and (D) leaves.

4. Phytochemistry of Lepidium sativum

Lepidium sativum L. is a phytochemically varied medicinal plant. Its nutritional, biological, and therapeutic properties are attributed to a wide variety of primary and secondary metabolites.¹² The plant portion (seeds, leaves, stems, and roots), geographic origin, environmental factors, growing conditions, and extraction techniques all affect Lepidium sativum's phytochemical content.³ It contains numerous bioactive compounds, such as alkaloids, flavonoids, phenolic compounds, terpenoids, volatile oils, fatty acids, proteins, amino acids, polysaccharides, vitamins, minerals, and glycosidic compounds¹² (Fig. 2).

Fig. 2.

Phytochemistry of Lepidium sativum.

Lepidium sativum's alkaloids are secondary metabolites that contain nitrogen and enhance its medicinal activity. These compounds have been linked to antioxidant, anti-inflammatory, antibacterial, and analgesic properties by modifying oxidative stress and inflammatory reactions.¹⁶ Garden cress's primary polyphenolic constituents are flavonoids, which include kaempferol, quercetin, and their glycosidic derivatives.³ These compounds demonstrate potent antioxidant activity and help prevent oxidative and inflammatory disorders by scavenging reactive oxygen and nitrogen species, boosting endogenous antioxidant defense systems, and controlling inflammatory pathways, especially nuclear factor kappa B (NF-κB).⁶

Lepidium sativum is rich in phenolic compounds, such as phenolic acids and related polyphenols, which significantly increase its antioxidant ability.⁷ These compounds protect biological components from oxidative damage by neutralizing free radicals, reducing lipid peroxidation, and preserving redox equilibrium. Additionally, phenolic components promote the plant's therapeutic significance by contributing to antibacterial, anti-inflammatory, and tissue-protective properties.¹⁷ Lepidium sativum is distinguished by its sulfur-containing glucosinolates, which myrosinase hydrolyzes enzymatically to produce physiologically active isothiocyanates.¹⁸ These metabolites have a significant role in the plant's chemoprotective, antioxidant, antibacterial, and anti-inflammatory properties. Isothiocyanates regulate cellular defense systems by triggering antioxidant response pathways, modifying detoxification enzymes, and controlling inflammatory processes.¹⁹

Lepidium sativum's distinctive scent and biological activity are influenced by terpenoids and volatile components. These compounds have shown antibacterial, antioxidant, and anti-inflammatory properties. They may help protect the respiratory system by regulating smooth muscle reactions and airway inflammation.²⁰ The plant's pharmacological potential is further enhanced by the variety of volatile compounds found in the essential oil fraction.³ Garden cress seeds, which are very rich in lipid content, contain fatty acids like α-linolenic acid (omega-3 fatty acid), linoleic acid (omega-6 fatty acid), oleic acid, and other unsaturated fatty acids.² These fatty acids may reduce inflammatory reactions by reducing lipid-derived mediators involved in immune modulation.²

Additionally, significant properties of proteins, essential amino acids, and mucilaginous polysaccharides are present in Lepidium sativum seeds.² The polysaccharide fraction's notable swelling and water-retention qualities support its conventional uses. These macromolecules may also have physiologic, immunomodulatory, and protective effects through interactions with cellular and immunological systems.²¹ Lepidium sativum is a source of vitamins, minerals, and secondary metabolites. It has B-complex vitamins, carotenoids (provitamin A molecules), and vitamin C, all of which support metabolic control and antioxidant defense.²² It also contains minerals that contribute to its nutritional value, such as calcium, iron, phosphorus, potassium, magnesium, zinc, and other trace elements.²³

Tannins, saponins, steroids, and glycosidic substances are other phytoconstituents found in Lepidium sativum.¹⁰ Tannins contribute to antioxidant, antibacterial, and astringent properties, as well as immunomodulatory, anti-inflammatory, and membrane-interacting activities.⁷ The plant's many biological functions are also influenced by glycosides and steroidal substances.⁷

5. Pharmacological activities of Lepidium sativum

The many phytoconstituents that give Lepidium sativum L. a wide range of pharmacological properties include flavonoids, phenolic compounds, glucosinolates, alkaloids, terpenoids, fatty acids, and polysaccharides.³ These bioactive compounds exhibited antioxidant, anti-inflammatory, antimicrobial, antidiabetic, hepatoprotective, cardioprotective, gastroprotective, analgesic, antipyretic, immunomodulatory, anticancer, and respiratory protective properties.⁶ The major pharmacological activities of Lepidium sativum include (Table 1, Table 2, Table 3, Table 4; Fig. 3):

Table 1.

Comparative summary of Lepidium sativum phytochemicals, mechanisms, and pharmacological activities.

Biological activity	Experimental model	Plant part used	Extraction method	Major phytochemical constituents	Proposed molecular mechanism	References
Antioxidant	In vitro	Seeds	Methanol, ethanol	Linolenic acid, oleic acid, β-sitosterol, γ-tocopherol, phenolics	Free-radical scavenging and ferric reducing activity mediated by phenolic compounds.	Chatoui et al.24
Antioxidant	In vitro	Shoot, leaf, stem, seed	Ethanol	Not identified	Increased GST, GSH, vitamin C, and reducing capacity.	Malar et al.25
Antioxidant, cytoprotective	In vitro (HepG2) and in vivo	Seeds	Chloroform	Not fully characterized	Reduced ROS and lipid peroxidation, preserved mitochondrial function, increased GSH.	Bin Jardan et al.26
Antidiabetic, cytoprotective	HFD/STZ diabetic mice	Seeds	Seed extract	Not reported	Improved pancreatic and hepatic protection, reduced hyperglycemia.	Desai et al.27
Anti-inflammatory	Carrageenan-induced paw edema	Seeds	Ethanol	Not identified	Reduced inflammatory mediators and edema.	Yahla et al.28
Antioxidant, anti-inflammatory	In vitro and in vivo	Seed coat mucilage	Polysaccharide fraction	Galacturonic acid, glucuronic acid, rhamnose, arabinose, maltose	ROS scavenging and suppression of inflammatory responses.	Khan et al.29
Analgesic	Writhing and hot-plate tests	Whole plant	Aqueous	Not identified	Peripheral and central antinociceptive activity.	Özdemir et al.30
Analgesic	Writhing, formalin, tail-flick tests	Seeds	Crude extract	Not identified	Inhibition of neurogenic and inflammatory pain pathways.	Raval & Ravishankar31
Anti-arthritic	FCA-induced arthritis rats	Seeds	Seed powder	Not reported	Reduced joint inflammation and tissue damage.	Nita et al.32
Osteoprotective	Ovariectomized rats	Whole plant	Hydroalcoholic extract	Glucosinolates, lignans, coumarins, phenolic acids, alkaloids	RANKL/OPG modulation, antioxidant enzyme activation, inhibition of bone resorption.	Abdallah et al.33
Antibacterial	In vitro antibacterial	Seeds	Ethanol, methanol, chloroform	Not identified	Likely bacterial membrane disruption.	Besufekad et al.34
Antibacterial	Clinical P. aeruginosa isolates	Seeds	Aqueous, ethanol	Not identified	Mechanism not investigated.	Margan et al.35
Anti-MRSA	In vitro and molecular docking	Leaves	Methanol	Five GC–MS compounds	PBP2a inhibition and impaired cell-wall synthesis.	36)
Antifungal, antioxidant, anticancer	In vitro	Leaves	Green-synthesized ZnO nanoparticles	ZnO nanoparticles with plant phytochemicals	Oxidative damage, membrane disruption, synergism with nystatin.	Yassin et al.37
Anticancer	Cell culture (PC3, A-549, Caco-2, HepG2)	Leaves, roots	Petroleum ether fractions	Glucosinolates and volatile compounds	Increased BAX/caspase-3, decreased BCL2, S-phase arrest.	Ibrahim et al.38
Anticancer	HCT116 and SW620 cells	Leaves	Leaf extract	Ten GC–MS compounds	DNA damage response, DDIT3 and GADD45G activation, MPG suppression.	Watyan et al.39
Anticancer	AOM/DSS colorectal cancer mice	Seeds	Seed extract	Not reported	p53 activation, apoptosis induction, reduced tumor formation.	Hussien & Alsulami40
Antidiabetic	Alloxan diabetic rats	Shoot, leaf, stem, seed	Ethanol	Not identified	Improved glucose homeostasis through antioxidant effects.	Malar et al.41
Antidiabetic, antioxidant	α-Glucosidase assay and diabetic mice	Seeds	Seed oil, aqueous and organic fractions	Not fully characterized	α-Glucosidase inhibition, increased GSH, reduced xanthine oxidase.	Sobhi et al.42
Antidiabetic	STZ diabetic rats	Whole plant	Extract	Not identified	Reduced oxidative stress and improved glucose metabolism.	Mishra et al.43
Antidiabetic	Alloxan diabetic rats	Seeds	Total alkaloid extract	Lepidine, semilepidine	Improved glucose and lipid metabolism.	Shukla et al.44
Antidiabetic	Normal and diabetic rats	Seeds	Aqueous extract	Not reported	Insulin-independent glucose-lowering effect.	Eddouks et al.45
Thyroid inhibitory	Male Wistar rats	Seeds	Ethanol	Not identified	Reduced T3/T4 and increased TSH.	Sciarrillo et al.46
Cardioprotective	5-FU cardiotoxicity in rats	Seeds	Seed powder	Not reported	Antioxidant and anti-inflammatory cardioprotection.	Mohamed and Safwat47
Antihypertensive, diuretic	Hypertensive and normotensive rats	Seeds	Aqueous extract	Not reported	Increased natriuresis and diuresis, reduced systolic blood pressure.	Maghrani et al.48
Antiulcer, gastroprotective	Pylorus ligation, NSAID-induced, and water immersion stress-induced gastric ulcer models in Wistar rats	Seeds	Ethanolic extract	Not identified	Reduced gastric acid secretion, increased gastric pH, and enhanced gastric mucosal protection.	Sivaramakrishna and Sravani49
Antiulcer, anti-H. pylori, antioxidant	In vitro anti-Helicobacter pylori assay and in vivo ulcer model	Seeds	Methanolic extract	Phenolic compounds (HPLC identified)	Antimicrobial activity against H. pylori, antioxidant effects, inhibition of lipid peroxidation, suppression of inflammation and apoptosis, and preservation of gastric mucosal integrity.	Salem et al.50
Antidiarrheal, antispasmodic	Castor oil-induced diarrhea in rats and isolated rat ileum	Seeds	Crude extract	Not characterized	Muscarinic receptor antagonism and Ca2+ channel blockade reduced intestinal smooth muscle contraction.	4, 5)
Antidiarrheal, antispasmodic	Castor oil-induced diarrhea in mice and isolated GI tissues from rats, guinea pigs, and rabbits	Seeds	Crude extract	Not characterized	Muscarinic receptor inhibition, Ca2+ channel blockade, K+ channel activation, and phosphodiesterase inhibition decreased gastrointestinal motility.	Gilani et al.51
Prokinetic, laxative	Mice and isolated gut tissues from mice, guinea pigs, and rabbits	Seeds	Aqueous–methanolic extract	Alkaloids, saponins, anthraquinones	Activation of muscarinic receptors stimulated intestinal smooth muscle contraction.	Mehmood et al.52
Hepatoprotective	D-GalN/LPS-induced fulminant hepatic failure in rats	Seeds	Ethanolic extract	Not fully characterized	Reduced oxidative stress, inhibited NF-κB, TNF-α, IL-6, iNOS, MPO, and HO-1, increased IL-10 and Bcl-2, and suppressed caspase-3-mediated apoptosis.	Raish et al.53
Nephroprotective	Cisplatin-induced acute renal failure in rats	Seeds	Ethanolic extract	Not identified	Enhanced antioxidant defense, reduced lipid peroxidation, restored Na+/K+-, Ca2+-, and Mg2+-ATPase activities, and improved renal function.	Yadav et al.54
Nephroprotective, antidiabetic	Streptozotocin-induced diabetic nephropathy in rats	Whole plant	Aqueous extract	Not identified	Suppressed NF-κB, TNF-α, IL-6, and TGF-β1, enhanced SOD, CAT, and GSH, reduced MDA, and improved renal function.	Alsuliam et al.55
Diuretic	Normal rats	Seeds	Aqueous and methanolic extracts	Not identified	Increased urine volume and sodium excretion; modulation of renal electrolyte handling.	Patel et al.56
Neuroprotective	Cadmium-induced memory impairment in Wistar rats	Whole plant	Extract	Not identified	Reduced acetylcholinesterase activity, improved cholinergic neurotransmission, and attenuated oxidative stress.	Ed-Day et al.57
Neuroprotective	AlCl₃-induced Alzheimer's disease model in rats	Seeds	Seed extract	Not identified	Antioxidant, anti-inflammatory, anti-apoptotic effects, reduced AChE activity, and improved neuronal survival.	Balgoon58
Wound healing	STZ-induced diabetic excision wound model in rats	Seed	Ethanolic extract (oral and topical)	Not identified	Enhanced collagen synthesis and extracellular matrix formation through antioxidant, anti-inflammatory, and antihyperglycemic effects.	Sahane et al.59
Osteoprotective	Ovariectomized osteoporosis model in rats	Whole plant	Hydroalcoholic extract	Glucosinolates, lignans, coumarins, phenolic acids, alkaloids	Regulated RANKL/OPG signaling, increased osteocalcin, SOD, and GPx, and reduced bone resorption markers.	Abdallah et al.33
Osteoprotective	Glucocorticoid-induced osteoporosis in guinea pigs	Seeds	Seed extract	Not identified	Reduced osteoclast activity and osteocyte apoptosis, preserved collagen, promoted osteoblast activity, and improved bone remodeling.	El-Haroun et al.60
Anti-PCOS, fertility-enhancing	Letrozole + high-fat diet-induced PCOS in rats	Seeds	Seed extract	Not identified	Improved insulin resistance, oxidative stress, inflammation, hormonal imbalance, ovarian morphology, and reproductive function.	Moustafa et al.61
Reproductive protective	Sulpiride-induced hyperprolactinemia in male mice	Whole plant	Aqueous extract	Not identified	Reduced prolactin, increased FSH and testosterone, improved spermatogenesis and sperm quality.	Ibraheem et al.62
Bronchodilator	Isolated guinea pig tracheal preparations	Seeds	Crude extract	Not characterized	Anticholinergic activity, Ca2+ channel blockade, and phosphodiesterase inhibition enhanced airway smooth muscle relaxation.	Rehman et al.4, 5
Bronchodilator, anti-asthmatic	Clinical study in patients with mild-to-moderate bronchial asthma	Seeds	Seed powder	Not characterized	Improved pulmonary function (FEV₁, FVC, FEF25–75%, MVV), likely through bronchodilation mediated by anticholinergic and phosphodiesterase inhibitory effects.	Paranjape & Mehta63

Table 2.

In vivo experimental studies on the pharmacological activities of Lepidium sativum L.

Dose/Concentration	Duration	Major findings	Critical appraisal	Reerences
NR	28 days	Reduced glucose and improved liver/pancreas damage	Short duration; limited mechanism	Desai et al.27
50 mg/kg	Acute	Reduced edema (40.44 ± 16.36%) and inflammation	Single dose; limited mechanisms	Yahla et al.28
20 mg/kg	Acute	Reduced writhing and increased pain latency	Small sample; single dose	Özdemir et al.30
NR	NR	Showed analgesic effects in multiple pain models	Active compounds unclear	Raval and Ravishankar31
NR	NR	Moderate anti-arthritic effect with radiological improvement	Limited histological recovery	Nita et al.32
50 and 100 mg/kg	NR	Prevented bone loss and regulated RANKL/OPG	Clinical validation needed	Abdallah et al.33
NR	28 days	Seed and leaf extracts reduced glucose	Limited phytochemical data	Malar et al.41
100 mg/kg	21 days	Reduced glucose and oxidative stress	Human validation needed	Sobhi et al.42
20 mg/kg	16 days	Improved glucose and biochemical markers	Small sample; short duration	Mishra et al.43
50–250 mg/kg	21 days	Reduced glucose and lipid abnormalities	The mechanism needs confirmation	Shukla et al.44
20 mg/kg	Acute/chronic	Lowered glucose without insulin increase	Molecular pathway unclear	Eddouks et al.45
200 mg/kg	21 days	Reduced T3/T4 and altered thyroid tissue	Single dose; limited translation	Sciarrillo et al.46
550 mg/kg/day	8 days	Protected against cardiac oxidative injury	Animal evidence only	Mohamed and Safwat47
20 mg/kg/day	3 weeks	Reduced blood pressure and increased diuresis	Limited dose evaluation	Maghrani et al.48
200–400 mg/kg	NR	Reduced ulcer index and improved gastric protection	Mechanism not studied	Sivaramakrishna and Sravani49
150–300 mg/kg	NR	Reduced oxidative stress, inflammation, and liver damage	Clinical studies needed	Raish et al.53
400 mg/kg	NR	Improved renal markers and antioxidant status	No histopathology	Yadav et al.54
250 mg/kg	8 weeks	Improved renal function and reduced inflammation	Animal model limitation	Alsuliam et al.55
50–100 mg/kg	Short-term	Increased urine output and electrolyte excretion	Long-term safety unknown	Patel et al.56
20 mg/kg	NR	Improved memory and reduced AChE changes	No molecular analysis	Ed-Day et al.57
20 mg/kg	8 weeks	Improved cognition and reduced oxidative/inflammatory damage	Model limitation	Balgoon58
20–30 mg/kg	NR	Enhanced wound closure and collagen formation	No clinical validation	Sahane et al.59
300 mg/kg	NR	Improved bone structure and reduced resorption	No clinical trial	El-Haroun et al.60
250–500 mg/kg	4 weeks	Improved fertility, hormones, and ovarian changes	Human evidence lacking	Moustafa et al.61
NR	NR	Improved testosterone, sperm count, and fertility parameters	Small sample; limited phytochemistry	Ibraheem et al.62

Table 3.

In vitro and ex vivo evidence of pharmacological activities of Lepidium sativum L.

Dose/Concentration	Duration	Major findings	Critical appraisal	References
NR	NR	High antioxidant activity; the shoot showed the highest DPPH activity (12.19 ± 0.02%)	Multiple assays used; no in vivo validation.	Malar et al.25
MIC 6.25–12.5 mg/mL	NR	Demonstrated antibacterial activity, especially against E. coli.	Further toxicity and in vivo validation needed.	Besufekad et al.34
25–100 mg/mL	NR	Active against MDR strains; aqueous extract showed higher activity (66%).	Limited isolates and mechanism analysis.	Margan et al.35
HepG2 IC₅₀ = 47.5 μg/mL	NR	Induced apoptosis via BAX/BCL2 regulation and caspase-3 activation.	In vitro findings require in vivo confirmation.	Ibrahim et al.38
Dose-dependent	NR	Reduced cell viability and modulated DNA repair genes.	Requires biological validation	Watyan et al.39
MIC 15 μg/mL; docking −7.1 and − 6.3 kcal/mol	NR	Showed antibacterial activity with promising docking interactions.	No animal studies available.	Mohammed Al-maaqar et al.36
MIC 125 and 62.5 μg/mL	NR	Antifungal activity with synergism with nystatin.	No in vivo validation.	Yassin et al.37
0.03–0.3 mg/mL	NR	Bronchodilator activity through Ca2+ blockade and PDE inhibition.	Isolated tissue model only; clinical relevance unclear.	Rehman et al.4, 5

Table 4.

Combined In Vitro and In Vivo evidence of pharmacological activities of Lepidium sativum L.

Dose/Concentration	Duration	Major findings	Critical appraisal	References
NR	NR	Demonstrated antioxidant and cytoprotective effects	Pharmacokinetic and clinical studies are needed	Bin Jardan et al.26
EC₅₀: 57.41 μg/mL; anti-inflammatory activity: 92.60%	NR	Exhibited antioxidant and anti-inflammatory activities	Mechanistic validation and safety studies are required	Khan et al.29
NR	NR	Showed anti-H. pylori and gastroprotective effects	Active compounds require further identification	Salem et al.50
NR	NR	Produced antidiarrheal and antispasmodic effects through muscarinic blockade and Ca2+ inhibition	No clinical evidence available	Rehman et al.4, 5
NR	NR	Demonstrated antidiarrheal effects with species-dependent mechanisms	Clinical translation remains uncertain	Gilani et al.51
NR	NR	Exhibited laxative and prokinetic effects via cholinergic mechanisms	Human studies are lacking	Mehmood et al.52
NR	NR	Showed antidiabetic effects through α-glucosidase inhibition and glucose reduction	Human validation is required	Sobhi et al.42

Abbreviations: EC₅₀, half-maximal effective concentration; Ca²⁺, calcium ion; H. pylori, Helicobacter pylori; NR: Not reported.

Hint:Lepidium sativum exhibits diverse pharmacological activities supported by preclinical and limited clinical evidence. Reported effects include antioxidant, anti-inflammatory, antimicrobial, antidiabetic, cardioprotective, hepatoprotective, gastroprotective, respiratory protective, analgesic, antipyretic, wound-healing, immunomodulatory, neuroprotective, nephroprotective, antihypertensive, antidiarrheal, anthelmintic, osteoprotective, and reproductive health-promoting activities. Most evidence is derived from in vitro and in vivo studies, while clinical evidence remains limited. A clinical study demonstrated bronchodilatory effects in asthmatic patients.⁶³ However, further well-designed clinical trials are required to confirm efficacy, safety, optimal dosage, and therapeutic applicability.

Fig. 3.

Pharmacological activities, phytochemicals, and mechanisms of action of Lepidium Sativum.

5.1. Antioxidant and cytoprotective activities

5.1.1. Antioxidant activity

Lepidium sativum has strong antioxidant activity due to its high concentration of phenolic compounds, flavonoids, glucosinolates, isothiocyanates, tocopherols, carotenoids, vitamin C, and other phytochemicals.¹² These bioactive compounds scavenge reactive oxygen and nitrogen species, prevent lipid peroxidation, chelate transition metal ions, and strengthen endogenous antioxidant defenses.¹² Lepidium sativum uses these mechanisms to reduce oxidative stress and protect cellular lipids, proteins, and Deoxyribonucleic acid (DNA) from oxidative damage.⁶⁴ Chatoui et al.²⁴ conducted an in vitro experimental study to evaluate the chemical composition and antioxidant capacity of Lepidium sativum seeds from four regions of Morocco. Seed moisture content and oil yield were 9.24–9.88% and 19.13–19.94% dry weight, respectively. The seeds contained fatty acids, sterols, and tocopherols, with linolenic acid (33%), oleic acid (23%), β-sitosterol (50%), and tocopherols (1500–1900 mg/kg; mainly γ-tocopherol) as major components. Folin–Ciocalteu, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay, iron-chelating assay, and Ferric Reducing Antioxidant Power (FRAP) assays demonstrated antioxidant activity. The methanol extract showed stronger reducing and radical-scavenging activity than the ethanol extract. Antioxidant activity was significantly correlated with total phenolic content. The study provided a comprehensive antioxidant evaluation, but its in vitro design requires further in vivo and clinical confirmation.

Malar et al.²⁵ evaluated the antioxidant activity of ethanolic extracts from different parts of Lepidium sativum, such as shoot, leaf, stem, and seed, in vitro. Shoot extract showed the highest DPPH radical scavenging activity (12.19 ± 0.02%), while stem extract showed the lowest (2.69 ± 0.05%). Seed extract had the highest glutathione-S-transferase activity (9600 ± 56.3 μg/mL), and leaf extract showed the highest reduced glutathione content (9 ± 0.2 μg/mL). All extracts demonstrated Fe³⁺–Fe²⁺ reducing ability, with shoot extract having the highest vitamin C content. However, the study lacked active compound identification and in vivo validation. Bin Jardan et al.²⁶ investigated the antioxidant and cytoprotective effects of Lepidium sativum seed extract using in vitro and in vivo models. Chloroform seed extract (5–25 μg/mL) protected human hepatocellular carcinoma cells (HepG2) cells against hydrogen peroxide (H₂O₂)-induced oxidative stress. At 25 μg/mL, it increased cell viability by 48%, reduced reactive oxygen species (ROS) generation by 45% and lipid peroxidation by 56%, increased mitochondrial membrane potential by 55%, and reduced glutathione levels by 46%. The combined cellular and animal models strengthened evidence for antioxidant and protective effects, but further pharmacokinetic, safety, and clinical studies are needed.

These studies consistently demonstrate the antioxidant potential of Lepidium sativum. However, variations in extraction methods, plant parts, antioxidant assays, and experimental models likely explain differences in the reported activities.24, 25, 26 Although the combined in vitro and in vivo approach used by Bin Jardan et al.²⁶ provides stronger translational evidence than in vitro studies alone, the current evidence remains predominantly preclinical.

5.1.2. Cytoprotective activities

Lepidium sativum demonstrates a significant cytoprotective effect by protecting cells and tissues against oxidative stress, inflammation, toxic assaults, and metabolic disorders.⁶ Its glucosinolates, isothiocyanates, flavonoids, phenolic acids, alkaloids, saponins, tannins, vitamins, and minerals are mostly responsible for this action.¹² Lepidium sativum inhibits NF-κB-mediated inflammatory signaling, activates the Nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway, regulates apoptosis by preserving the balance between pro- and anti-apoptotic proteins, lowers caspase activation, and preserves cellular redox homeostasis.3, 65 Desai et al.²⁷ conducted an experimental animal study to evaluate the antihyperglycemic and cytoprotective effects of Lepidium sativum seed extract (LSE) in obesity-associated diabetes. High-fat diet (HFD)-streptozotocin (STZ)-induced type 2 diabetic mice were treated with LSE for 28 days. LSE significantly reduced blood glucose levels, improved body weight changes, and reversed degenerative alterations in hepatic and pancreatic tissues. The findings demonstrated the antihyperglycemic and cytoprotective potential of LSE. However, the short study duration and reliance on an animal model limit direct clinical applicability.

5.2. Anti-inflammatory and analgesic activities

5.2.1. Anti-inflammatory activity

The bioactive compounds of Lepidium sativum, such as flavonoids, phenolic compounds, glucosinolates, isothiocyanates, alkaloids, tannins, and essential fatty acids, show notable anti-inflammatory activities.⁷ These phytochemicals suppressed pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nitric oxide (NO), and prostaglandin E₂ (PGE₂).⁶⁶ Furthermore, Lepidium sativum enhances endogenous antioxidant defenses and inhibits activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, reducing inflammation and oxidative stress.7, 12 Yahla et al.²⁸ evaluated Lepidium sativum seed ethanolic extract (EELS) in carrageenan-induced paw edema in mice (25 ± 5 g). EELS (50 mg/kg) reduced edema by 40.44 ± 16.36% after 6 h and improved serum albumin, C-reactive protein (CRP), and plasma fibrinogen versus a comparator. The validated model supports anti-inflammatory activity, however the single-dose design and acute inflammation model limit clinical translation.

Khan et al.²⁹ assessed seed-coat mucilage prepared from Lepidium sativum polysaccharides using antioxidant assays and carrageenan-induced edema. Fraction F53 showed the highest antioxidant activity (EC₅₀ = 57.41 ± 1.34 μg/mL) and anti-inflammatory activity (92.60%) compared with diclofenac (91.46%). Gas chromatography–mass spectrometry (GC–MS) identified major acidic sugars (galacturonic and glucuronic acids) and neutral sugars (rhamnose, arabinose, and maltose). Compared with the ethanolic extract, the mucilage fraction showed greater anti-inflammatory activity, although both findings require mechanistic and clinical validation.

5.2.2. Analgesic (antinociceptive) activity

Lepidium sativum has long been used to treat pain associated with inflammatory diseases, musculoskeletal problems, and tissue damage because of its strong analgesic (antinociceptive) effect.¹⁵ Bioactive components such as flavonoids, phenolic compounds, alkaloids, glucosinolates, and essential fatty acids are mainly responsible for its analgesic effects. These phytochemicals suppress the COX and lipoxygenase (LOX) pathways and reduce the synthesis of pro-inflammatory mediators, including prostaglandins, TNF-α, IL-1β, and IL-6.³ Özdemir et al.³⁰ evaluated the antinociceptive activity of aqueous extract of Lepidium sativum L. in Swiss albino male mice using acetic acid-induced writhing and hot plate tests. Three groups (n = 6) received the extract (20 mg/kg) 30 min before pain induction, which significantly increased reaction time and reduced writhing responses, with a maximum 27.0% reduction compared with the comparator and diclofenac sodium (50 mg/kg). The study supports analgesic potential, but the small sample size and single dose limit dose–response evaluation.

Raval and Ravishankar³¹ assessed the analgesic effect of Lepidium sativum Linn. seeds in albino rats and Swiss albino mice using acetic acid-induced writhing, formaldehyde-induced paw licking, and tail-flick tests. Therapeutic and double doses significantly increased latency in writhing, inhibited neurogenic pain at the double dose and inflammatory pain at the therapeutic dose, and showed mild-to-moderate tail-flick activity. Multiple pain models strengthen the findings, but limited mechanistic evaluation and phytochemical analysis restrict identification of active constituents. Although both studies support the analgesic potential of Lepidium sativum, variations in animal models, extracts, and dosing approaches may explain differences in observed effects.30, 31 However, the use of acute pain models and limited mechanistic data restricts direct translation to human clinical applications.30, 31

5.2.3. Antiarthritic activity

Lepidium sativum demonstrates promising antiarthritic properties through mechanisms like reducing joint inflammation and tissue damage. Bioactive compounds, including flavonoids, phenolic compounds, glucosinolates, alkaloids, and essential fatty acids, which support its anti-inflammatory, antioxidant, and immunomodulatory qualities, are mostly responsible for its therapeutic effects.7, 12 These phytochemicals reduce synovial inflammation and limit inflammatory joint damage by suppressing the production of pro-inflammatory mediators such as prostaglandin E2 (PGE2), IL-1β, IL-6, COX-2, and TNF-α.12, 66, 67 Lepidium sativum reduces the expression of inflammatory genes and immune-mediated joint degradation by blocking inflammatory signaling pathways, including NF-κB.⁷ Nita et al.³² evaluated Lepidium sativum L. seed powder in Freund's complete adjuvant-induced arthritis rats. The study assessed paw oedema and proximal interphalangeal joint histopathology. Treatment improved radiological changes, but histology showed persistent bone/cartilage degeneration, erosion, and inflammation. Lower doses showed moderate anti-arthritic effects, whereas higher doses had inconsistent responses. The study supports anti-arthritic potential, but limited tissue recovery requires further mechanistic studies. Moreover, findings from acute pain models in mice may not fully predict efficacy in chronic human pain conditions.

Abdallah et al.³³ investigated the effects of Lepidium sativum extract in ovariectomized rats at doses of 50 and 100 mg/kg, with 17β-estradiol as a comparator. The extract prevented bone loss, improved femur strength, increased LDH and osteocalcin, preserved superoxide dismutase (SOD), and glutathione peroxidase (GPx), reduced lipid peroxidation, decreased C-terminal telopeptide of type I collagen (CTX—I) and TRAP, and regulated the Receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) pathway. Ultra-High-Performance Liquid Chromatography (UHPLC) coupled with Photodiode Array Detection (PDA) and Electrospray Ionization–Mass Spectrometry (ESI–MS) identified glucosinolates, lignans, coumarins, phenolic acids, and alkaloids. Solid-Phase Microextraction (SPME)-GC/MS identified compounds contributing to osteoprotective activity. The study has strong biochemical and metabolomic evidence supporting bone protection, but human clinical studies are needed to confirm efficacy and safety. Differences in animal species, pain models, and dosing strategies may contribute to variability in observed effects.

5.3. Antimicrobial activities

5.3.1. Antibacterial activity

Both Gram-positive and Gram-negative bacteria are susceptible to the broad-spectrum antibacterial activity of Lepidium sativum. Its high concentration of glucosinolates, isothiocyanates, flavonoids, alkaloids, tannins, phenolic acids, and other bioactive phytochemicals is mainly responsible for this antibacterial activity.7, 68 These compounds prevent the growth of bacteria through a variety of mechanisms, such as disruption of bacterial cell membranes, increased membrane permeability, interference with vital metabolic enzymes, inhibition of protein and nucleic acid synthesis, and induction of oxidative stress within bacterial cells.6, 7, 68 Besufekad et al.³⁴ evaluated ethanol, methanol, and chloroform seed extracts of Lepidium sativum against E. coli (ATCC 25922), K. pneumoniae (ATCC 27736), P. aeruginosa (ATCC 27853), S. aureus (ATCC 25923), and S. sonnei (ATCC 25931). Ethanol and methanol extracts showed the highest activity against E. coli (22.63 ± 0.7 mm), while the methanol extract showed the lowest against P. aeruginosa (9 ± 0.3 mm). Ethanolic extract showed Minimum Inhibitory Concentration (MIC) values of 6.25–12.5 mg/mL. Variations in bacterial susceptibility may be related to extract composition and organism-specific characteristics.

Margan et al.³⁵ assessed ethanolic and aqueous seed extracts prepared from Lepidium sativum against 30 multidrug-resistant (MDR) and 35 sensitive clinical isolates of P. aeruginosa. Activity was observed at 25–100 mg/mL. Among 130 isolates, 49 (37%) were susceptible, including 17/60 (28.3%) MDR and 32/70 (45.7%) sensitive isolates. Aqueous extract showed higher activity than ethanolic extract (43/65, 66% vs. 6/65, 9%). The small number of isolated compounds and the lack of mechanistic and phytochemical analyses limited the interpretation and clinical relevance of the findings.³⁶ identified Lepidium sativum leaf targeting methicillin-resistant staphylococcus aureus (MRSA) penicillin-binding protein 2a (PBP2a) using in vitro and in silico approaches. GC–MS identified 5 phytochemicals, and 2 compounds showed docking scores of −7.1 and − 6.3 kcal/mol. In vitro activity showed MIC of 15 μg/mL, inhibition zones of 12.3 ± 0.5–19 ± 0.5 mm, and significant concentration-dependent effects. Despite promising findings, in vivo validation, pharmacokinetic, and safety studies are required for clinical translation.

5.3.2. Antifungal activity

The bioactive compounds of Lepidium sativum, such as flavonoids, phenolic compounds, alkaloids, terpenoids, glucosinolates, and essential oil, are primarily responsible for its antifungal property.² These phytochemicals contribute to the prevention of fungal growth through a variety of mechanisms, such as disruption of fungal cell membrane integrity, interference with ergosterol biosynthesis, inhibition of oxidative stress responses, and reduction of fungal enzyme activity.37, 69 Its antioxidant and anti-inflammatory properties may improve host defense mechanisms against fungal infections by regulating oxidative stress and inflammatory responses.⁷ Yassin et al.³⁷ evaluated Lepidium sativum-mediated zinc oxide nanoparticles (ZnO-NPs), which have a 32 nm hexagonal wurtzite structure and dose-dependent antifungal activity against Candida albicans and C. tropicalis with MICs of 125 μg/mL and 62.5 μg/mL, respectively. ZnO-NPs with nystatin showed synergistic effects with fold area values of 0.85 and 0.99 and fractional inhibitory concentration index (FICI) values of 0.38 and 0.25. The nanoparticles also demonstrated antioxidant activity (IC₅₀: 335.48 μg/mL) and selective cytotoxicity against Human hepatoma cell line 7 (Huh7) cells (IC₅₀: 145.2 μg/mL) compared with WI38 cells (IC₅₀: 237.6 μg/mL), supporting their potential as antifungal agents and nystatin enhancers. However, these in vitro findings require validation in in vivo models, as nanoparticle behavior and safety may differ under physiological conditions.

5.4. Anticancer activities

Lepidium sativum has a variety of bioactive compounds, including glucosinolates, isothiocyanates, flavonoids, phenolic compounds, and alkaloids, which are thought to have anticancer potential.¹² These phytochemicals contribute to anticancer effects through a variety of mechanisms, such as suppression of angiogenesis, induction of apoptosis, inhibition of cancer cell proliferation, and modulation of signaling pathways involved in tumor development and progression.6, 29 Lepidium sativum's bioactive compounds can improve detoxification pathways, control cell cycle progression, and affect molecular targets like NF-κB, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and apoptotic regulators, all of which support the plant's potential role in cancer management and prevention.⁷⁰ Ibrahim et al.³⁸ conducted an in vitro study on Lepidium sativum cell cultures. Tyrosine and methionine increased glucosinolate accumulation, with 1H-Cyclopenta(b)pyridine-3‑carbonitrile-4,5,6,7-tetrahydro-2-methylthio-4 spirocyclohexane as the major glucosinolate. Petroleum ether fractions contained 15 compounds, mainly benzene-1,3,5-trimethyl (12.99%) in roots and benzene-2-ethyl-1,4-dimethyl (10.66%) in leaves. Extracts inhibited PC3, A-549, Caco-2, and HepG2 cells; leaf extract showed the highest activity against HepG2 (IC₅₀ = 47.5 μg/mL) through BAX increase, B-cell lymphoma 2 (BCL2) reduction, caspase-3 activation, and S-phase arrest. The study provided strong mechanistic evidence. However, in vitro findings may not fully reflect human responses, and the lack of normal cell and in vivo models limits translational interpretation.

Watyan et al.³⁹ conducted an in vitro molecular study of Lepidium sativum leaf extract against HCT116 and SW620 cells. The extract reduced viability dose-dependently, altered 84 DNA damage and repair genes, increased DNA damage-inducible transcript 3 (DDIT3) and growth arrest and DNA damage-inducible gamma (GADD45G), and decreased miles per gallon (MPG) expression. GC–MS identified 10 compounds with favorable Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties and Lipinski's Rule of Five adherence. Although molecular findings support anticancer potential, computational predictions require experimental validation, and cell models have limited ability to represent tumor complexity. Hussien and Alsulami⁴⁰ conducted an in vivo study using Azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colorectal cancer in male mice. L. sativum seed extract (200 mg/kg and 400 mg/kg) reduced tumor incidence, polyp number, tumor size, and tissue damage, increased p53 expression, promoted apoptosis, reduced phenolic compound extract (PCE) micronucleus formation, improved the PCE/normochromatic erythrocyte ratio, and decreased sperm abnormalities. Despite stronger translational relevance than in vitro studies, species differences and limited pharmacokinetic data restrict direct clinical application.

5.5. Metabolic and endocrine protective activities

5.5.1. Antidiabetic activity

Lepidium sativum demonstrates remarkable antidiabetic potential through pathways involving glucose metabolism, insulin sensitivity, oxidative stress management, and pancreatic β-cell protection.6, 12 The plant may lower postprandial glucose spikes, improve insulin signaling, block enzymes that break down carbohydrates like α-amylase and α-glucosidase, and increase glucose absorption.³³ Moreover, its antioxidant properties reduce the outcomes of diabetes and pancreatic dysfunction linked to oxidative stress. Additionally, Lepidium sativum affects lipid metabolism, improving metabolic regulation and preventing irregularities associated with diabetes.⁸ Malar et al.⁴¹ evaluated ethanolic extracts of shoot, leaf, stem, and seed of Lepidium sativum in alloxan-induced diabetic rats. Acute toxicity showed no mortality up to 1 g/kg. Blood glucose was evaluated on days 0, 7, 14, 24, and 28. Seed and leaf extracts significantly reduced fasting blood glucose levels comparable to metformin, whereas stem extract showed no significant effect, and whole plant extract showed moderate activity. Variations among plant parts suggest differences in bioactive compounds, but limited phytochemical analysis restricted mechanism interpretation.

Sobhi et al.⁴² studied Lepidium sativum seeds using in vitro and in vivo models. Aqueous and organic fractions inhibited α-glucosidase with IC₅₀ values of 300 and 9.375 μg/mL, respectively, compared with acarbose (388 μg/mL). Seed oil (100 mg/kg for 21 days) reduced blood glucose in STZ-induced diabetic Bagg Albino Laboratory-bred (BALB)/c mice (>400 mg/dL), increased glutathione (GSH), and reduced xanthine oxidase activity. The combined enzyme, animal, and oxidative assessments supported mechanisms, but human studies are lacking. Mishra et al.⁴³ evaluated the extract of Lepidium sativum in 30 Wistar rats with STZ-induced diabetes (45 mg/kg, i.p.). Extract (20 mg/kg for 16 days) reduced glucose, creatinine, alkaline phosphatase, cholesterol, and malondialdehyde, while improving DPPH and FRAP activities. However, the small sample size, short duration, and animal model limit translation to human diabetes.

Shukla et al.⁴⁴ evaluated total alkaloids from Lepidium sativum seed, lepidine, and semilepidine in alloxan-induced diabetic rats. Lepidium sativum seed extract (LSTA) (50, 150, and 250 mg/kg for 21 days) at 250 mg/kg significantly reduced blood glucose, cholesterol, triglycerides, and urea. Body weight increased by 1.94% compared with 6.14% in the normal control and 8.94% in the diabetic control. Dose evaluation and biochemical findings supported activity. Although dose-dependent effects were observed, molecular mechanisms and clinical relevance remain unclear. Eddouks et al.⁴⁵ investigated the aqueous extract of Lepidium sativum seed in normal and STZ-induced diabetic rats. The extract (20 mg/kg) significantly reduced blood glucose and normalized levels after 2 weeks. Reduction occurred in normal rats (acute and chronic) without changes in plasma insulin, showing an insulin-independent effect. The study supported glucose-lowering activity, but the molecular pathway remains unclear.

5.5.2. Thyroid-protective activity

Lepidium sativum has a rich phytochemical profile, including flavonoids, phenolic compounds, alkaloids, and other antioxidant compounds that may have thyroid-protective effects.² These bioactive compounds may support thyroid function by reducing oxidative stress, decreasing inflammatory reactions, and protecting thyroid tissue from cellular damage. Lepidium sativum extract may regulate hypothyroidism by enhancing thyroid-related biochemical parameters and protecting thyroid tissue from oxidative damage.⁷¹ Furthermore, Lepidium sativum may enhance overall physiological balance by endocrine control through metabolic pathways linked to hormone synthesis, cellular communication, and steroidogenic activity.2, 72 Sciarrillo et al.⁴⁶ evaluated ethanolic Lepidium sativum L. seed extract in male Wistar rats divided into 4 groups: control, Lepidium sativum extract (200 mg/kg i.p. for 21 days), T3-treated (25 μg/100 g i.p. for 21 days), and iopanoic acid-treated (100 mg/kg for 21 days). The extract significantly decreased serum T3 and T4 and increased thyroid-stimulating hormone (TSH) levels. Histology showed capillary congestion and dilation, cellular infiltration, follicular disintegration, and vacuolar degeneration. However, differences in experimental conditions and limited mechanistic evidence restrict interpretation. The study confirmed thyroid-inhibitory activity, but its interpretation was limited by the use of male rats, a single-dose design, and the lack of mechanistic and clinical validation. Translation to humans remains uncertain due to limited pharmacokinetic and clinical data.

5.6. Cardiovascular protective activities

5.6.1. Cardioprotective activity

The bioactive compounds of Lepidium sativum, such as flavonoids, phenolic compounds, alkaloids, glucosinolates, and essential fatty acids, are primarily responsible for the plant's possible cardioprotective effects.¹⁴ It supports cardiovascular health by lowering oxidative stress, strengthening antioxidant defense mechanisms, and stopping lipid peroxidation.⁷³ Lepidium sativum has been linked to decreased vascular oxidative damage, enhanced endothelial function, and defense against structural and functional changes in the heart.⁶,⁴⁷ evaluated Lepidium sativum seed powder against 5-fluorouracil (5-FU)-induced cardiotoxicity in albino rats. Rats received saline (control), 5-FU (150 mg/kg, intraperitoneally on day 5), or LS (550 mg/kg/day orally for 8 days) with 5-FU. 5-FU increased cardiac troponin I (cTnI), creatine kinase–myocardial band (CK-MB), lipid profile, cardiac malondialdehyde (MDA), myeloperoxidase (MPO), and IL-1β and decreased high-density lipoprotein cholesterol (HDL—C) and cardiac GSH. LS significantly reversed these changes through antioxidant and anti-inflammatory effects, demonstrating cardioprotective potential. However, translation to humans remains uncertain due to limitations of the animal model and the absence of clinical evidence.

5.6.2. Antihypertensive activity

The bioactive compounds of Lepidium sativum, including flavonoids, phenolic compounds, alkaloids, and glucosinolates, demonstrate antihypertensive potential. These compounds may help regulate blood pressure by enhancing vasodilation, increasing endothelial nitric oxide availability, reducing oxidative stress, and reducing inflammatory pathways linked to vascular dysfunction.⁷ Lepidium sativum may affect kidney processes related to fluid and electrolyte balance and lipid metabolism, protecting the heart and lowering blood pressure.3, 74 Maghrani et al.⁴⁸ assessed aqueous Lepidium sativum L. extract (20 mg/kg/day for 3 weeks) in Wistar–Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The extract reduced systolic blood pressure in SHR rats, starting from day 7, with no effect in WKY rats. It increased water excretion in WKY rats and urinary Na⁺, K⁺, and Cl⁻ excretion in WKY (Na⁺; K⁺/Cl⁻) and SHR rats (Na⁺; K⁺/Cl⁻). Glomerular filtration rate increased in WKY rats, without changes in SHR rats or heart rate. The study confirmed the antihypertensive and diuretic potential of Lepidium sativum. However, translation to humans is limited by the animal model, short duration, single-dose design, and absence of clinical evidence.

5.7. Gastrointestinal protective activities

5.7.1. Antiulcer activity

Lepidium sativum has shown antiulcer activity by mechanisms such as improving mucosal protection, reducing oxidative stress, and regulating inflammatory responses.⁷ Its bioactive compounds, flavonoids, alkaloids, terpenoids, phenolic compounds, and glucosinolates, contribute to gastroprotective effects by scavenging reactive oxygen species, boosting mucus secretion, and fortifying the stomach mucosal barrier.¹² Its anti-inflammatory properties are supported by lower inflammatory mediators associated with ulcers, and its antioxidant activity reduces cellular damage and lipid peroxidation.⁷ Sivaramakrishna and Sravani⁴⁹ evaluated the antiulcer activity of ethanolic Lepidium sativum L. seed extract in albino Wistar rats using pylorus ligation, nonsteroidal anti-inflammatory drug (NSAID)-induced, and water immersion stress-induced ulcer models. Oral doses of 200 and 400 mg/kg showed a dose-dependent gastroprotective effect, reducing ulcer index and increasing gastric juice pH. The use of multiple validated ulcer models supported the findings; however, the study lacked detailed molecular mechanisms and human clinical evidence. Furthermore, animal models may not fully predict human therapeutic outcomes.

Salem et al.⁵⁰ evaluated the anti-Helicobacter pylori and antiulcer effects of methanolic Lepidium sativum seed extract through in vitro and in vivo studies. HPLC identified phenolic compounds, and the extract showed antimicrobial and antioxidant effects. It reduced ulcer index, increased ulcer inhibition percentage, decreased lipid peroxidation, improved antioxidant markers, and suppressed inflammatory and apoptotic markers. Histopathology showed reduced epithelial erosion, restored enterocytes, and preserved gastric mucosal integrity. The study was strengthened by comprehensive phytochemical, biological, biochemical, and histological analyses. However, differences in extracts and models limit direct comparison, and clinical validation remains lacking.

5.7.2. Antidiarrheal and spasmolytic activity

Lepidium sativum's bioactive compounds, which include flavonoids, alkaloids, terpenoids, and phenolic compounds, are responsible for its antidiarrheal and spasmolytic effects.⁶ These phytochemicals may help control intestinal motility, reduce gastrointestinal spasms, and reduce excessive smooth muscle activity. L. sativum's antidiarrheal properties are associated with intestinal secretion regulation, suppression of inflammatory mediators, and enhancement of intestinal barrier function.¹⁰ Its spasmolytic activity may relax gastrointestinal smooth muscle, reduce abdominal cramping, and enhance intestinal comfort by controlling calcium-dependent pathways.⁷ Rehman et al.4, 5 evaluated a crude extract prepared from Lepidium sativum seeds for antidiarrheal and antispasmodic activities using castor oil-induced diarrhea in rats and isolated rat ileum. Lepidium sativum seed crude extract (100 and 300 mg/kg) reduced diarrhea, while 0.01–5 mg/mL inhibited carbachol- and K⁺-induced contractions by muscarinic receptor blockade and calcium channel inhibition. Its activity was comparable to dicyclomine and verapamil. However, the use of crude extract limits identification of active compounds, and animal models may not fully reflect human gastrointestinal responses. The study provided strong mechanistic evidence; however, animal findings, lack of compound-specific evaluation, and absence of human clinical studies limit translation.

Gilani et al.⁵¹ assessed species-dependent antidiarrheal and antispasmodic effects of L. sativum crude extract using castor oil-induced diarrhea in mice and isolated gastrointestinal tissues from rats, guinea pigs, and rabbits. Crude seed extract of Lepidium sativum at doses of 300 and 1000 mg/kg reduced diarrhea in mice by decreasing intestinal contractions. This effect was mediated through inhibition of muscarinic receptors, blockade of calcium channels, activation of potassium channels, and inhibition of phosphodiesterase activity, which collectively reduce gastrointestinal smooth muscle activity. Rat tissues showed the highest sensitivity. Although the multi-species model improved mechanistic understanding, species variability limits direct clinical translation. The multi-species and mechanistic approach strengthened evidence; however, species differences and lack of clinical trials require further validation.

5.7.3. Laxative activity

Lepidium sativum has long been used to promote bowel regularity and digestive health. Its laxative activity is associated with its high dietary fiber content, mucilaginous polysaccharides, and bioactive phytoconstituents that stimulate intestinal motility and help stool movement.³ The mucilage generated after hydration increases fecal volume, regulates water in the colon, and helps soften stools, hence aiding bowel movement.⁷⁵ Additionally, its phytochemicals may contribute to gastrointestinal stimulation and modulation of digestive function, with potential use in the management of constipation and related gastrointestinal discomfort.¹⁰ Mehmood et al.⁵² investigated the gastrointestinal activity of Lepidium sativum seed extract using mice and isolated gut tissues from mice, guinea pigs, and rabbits. The aqueous-methanolic extract at 30 and 100 mg/kg showed prokinetic and laxative effects with partial atropine inhibition. Lepidium sativum seed extract (0.1–1 mg/mL) produced dose-dependent contractions in isolated mouse and guinea-pig jejunum and ileum. These contractions were inhibited by atropine, indicating that the extract stimulates intestinal smooth muscle through muscarinic receptor activation. Rabbit jejunum showed no response to atropine, pyrilamine, or SB203186, while rabbit ileum showed partial atropine sensitivity. Alkaloids, saponins, and anthraquinones were identified. The study supports the traditional use of Lepidium sativum for digestive disorders such as indigestion and constipation. However, species-specific responses limit direct translation to humans, and the use of crude extracts with limited compound characterization, pharmacokinetic, safety, and clinical data.

5.8. Hepatorenal protective activities

5.8.1. Hepatoprotective activity

Lepidium sativum's antioxidant, anti-inflammatory, and free radical neutralization properties have shown hepatoprotective potential.¹² Its bioactive components, flavonoids, alkaloids, phenolic compounds, and glucosinolates, help to maintain hepatic integrity by reducing oxidative stress, improving endogenous antioxidant defense mechanisms, and reducing lipid peroxidation.¹² Lepidium sativum's anti-inflammatory and immunomodulatory properties may support liver protection by controlling inflammatory pathways and lowering oxidative-inflammatory damage.7, 53 Lepidium sativum may improve liver health and reduce hepatic damage brought on by oxidative stress and inflammatory processes.12, 53 Raish et al.⁵³ evaluated the hepatoprotective activity of Lepidium sativum ethanolic seed extract (LSEE) against D-GalN/LPS-induced fulminant hepatic failure in rats. LSEE (150 and 300 mg/kg) was compared with silymarin (25 mg/kg). LSEE reduced hepatic injury, biochemical alterations, and lipid peroxidation, restored antioxidant status, and improved liver histology. It downregulated TNF-α and IL-6 mRNA by 0.47- and 0.26-fold, increased IL-10 by 1.9- and 2.8-fold, and reduced iNOS, HO-1, MPO activity, and NF-κB activation in a dose-dependent. It also decreased caspase-3 and increased Bcl-2 expression, confirming antioxidant, anti-inflammatory, and anti-apoptotic hepatoprotective effects. The study provided strong biochemical, molecular, and histological evidence. However, the acute rat model may not fully represent human liver diseases, and differences in extract composition and dosing may limit direct comparison.

5.8.2. Nephroprotective activity

Lepidium sativum has antioxidant, anti-inflammatory, and free radical scavenger properties that demonstrate nephroprotective potential.¹⁴ Its bioactive compounds, flavonoids, alkaloids, phenolic compounds, and glucosinolates, help to maintain kidney function by lowering oxidative stress and inflammatory damage.⁶ The plant may reduce lipid peroxidation, strengthen endogenous antioxidant defense systems, and protect kidney cellular structures from oxidative damage.⁷ Its possible involvement in preserving kidney integrity and averting renal tissue damage is further supported by its capacity to enhance detoxification pathways and regulate inflammatory mediators.⁷⁶ Yadav et al.⁵⁴ evaluated the ethanolic extract of Lepidium sativum L. seed against cisplatin-induced acute renal failure in albino rats. Rats were divided into 4 groups (n = 6): control, cisplatin model (5 mg/kg, i.p.), curative, and protective groups receiving L. sativum extract (400 mg/kg). Cisplatin caused weight loss, increased urine output, urea, creatinine, and MDA, and altered the antioxidant defense system, with reduced Na⁺/K⁺-ATPase, Ca²⁺-ATPase, and Mg²⁺-ATPase activities. Lepidium sativum improved renal markers, antioxidant status, oxidative damage, and ATPase activities. The study showed nephroprotective and nephrocurative effects of antioxidant protection. However, limitations included small sample size, short duration, lack of histopathology, and molecular pathway analysis. Additionally, the acute cisplatin model may not fully represent human chronic kidney disease, limiting clinical translation.

Alsuliam et al.⁵⁵ investigated aqueous whole-plant Lepidium sativum extract in streptozotocin-induced diabetic nephropathy in rats. Animals were divided into 4 groups, and the extract was administered at 250 mg/kg for 8 weeks. Lepidium sativum reduced fasting blood glucose, increased fasting insulin, improved lipid abnormalities by reducing cholesterol, free fatty acids, triglycerides, and LDL-c, and decreased urinary volume, albumin excretion, and renal creatinine abnormalities. It improved tubular damage, reduced NF-κB, TNF-α, IL-6, and TGF-β1 expression, increased SOD, CAT, and GSH, and decreased MDA levels. The study demonstrated hypoglycemic, antioxidant, anti-inflammatory, and anti-fibrotic effects. However, limitations included animal-only evidence, lack of clinical confirmation, and absence of standardized dose-response evaluation. Differences in animal models and extract preparation make comparisons difficult.

5.8.3. Diuretic activity

The phytochemical composition of Lepidium sativum, including flavonoids, alkaloids, phenolic compounds, and minerals like potassium, may be responsible for its purported diuretic properties. These bioactive components may improve urine excretion by influencing renal function, encouraging electrolyte balance, and raising urine production.² Its historic use in disorders including urinary irregularities, edema, and fluid retention may be attributed to the diuretic effect, which is linked to enhanced fluid regulation.¹¹ Additionally, it may protect renal function by reducing oxidative stress and preventing kidney damage.¹¹ However, more research is needed to fully understand the specific molecular pathways underlying L. sativum's diuretic activity.

Patel et al.⁵⁶ evaluated the diuretic activity of aqueous and methanol extracts of Lepidium sativum seeds in normal rats. Extracts were administered orally at 50 and 100 mg/kg, with hydrochlorothiazide (10 mg/kg) as a positive control. Both extracts increased urine volume and sodium excretion. The aqueous extract (100 mg/kg) increased potassium excretion, while the methanol extract conserved potassium. No significant changes were observed in urine conductivity or pH. Both extractions have diuretic effects comparable to hydrochlorothiazide, supporting the traditional use of Lepidium sativum. The study confirmed the diuretic potential of Lepidium sativum seeds in animals. However, the findings are limited by the short-term animal model, lack of mechanistic evidence, and absence of clinical validation, which restrict their translation to human therapy.

5.9. Neuroprotective activities

Bioactive compounds of Lepidium sativum, including Flavonoids, alkaloids, phenolic compounds, and glucosinolates, demonstrate neuroprotective potential.² Its neuroprotective benefits are primarily linked to the reduction of oxidative stress, the suppression of neuroinflammatory reactions, the control of apoptotic pathways, and the maintenance of neuronal integrity.⁷⁷ Lepidium sativum's antioxidant properties help prevent the formation of reactive oxygen species and protect brain cells from oxidative injury.⁷⁷ Additionally, Lepidium sativum may enhance endogenous antioxidant defense mechanisms, regulate neurotransmitter balance, and alter signaling pathways that are crucial for neuronal survival, such as the Wnt/β-catenin/CaMK-II signaling cascade.77, 78

Ed-Day et al.⁵⁷ evaluated the neuroprotective effects of Lepidium sativum L. against cadmium-induced memory impairment in Wistar rats. Groups received control, CdCl₂ (10 mg/kg), or CdCl₂ (10 mg/kg) + LS extract (20 mg/kg). Cadmium reduced short-term and long-term memory (p < 0.05) and increased acetylcholinesterase (AChE) activity in the hippocampus, cerebellum, and cortex (p < 0.001). LS improved memory and reduced cholinergic dysfunction. The study was supported by behavioral and biochemical findings but was limited by animal models, small sample sizes, and a lack of molecular pathway analysis. Balgoon⁵⁸ studied Lepidium sativum seed extract in an AlCl₃-induced Alzheimer's disease rat model. Forty rats were assigned to four groups (n = 10): control, LS-treated (20 mg/kg for 8 weeks), AD-induced (AlCl₃ 10 mg/kg), and LS-treated AD groups. AlCl₃ impaired memory, increased oxidative stress, inflammatory cytokines, AChE activity, and neuronal damage. Lepidium sativum improved cognition, antioxidant defense, and reduced inflammation, and alleviated cortical damage through antioxidant, anti-inflammatory, and antiapoptotic mechanisms. The study was strengthened by behavioral, biochemical, and histological assessments but limited by the incomplete similarity of the AlCl₃ model to human Alzheimer's disease and unclear long-term safety, pharmacokinetics, and clinical effectiveness.

5.10. Tissue repair and musculoskeletal protective activities

5.10.1. Wound-healing activity

Lepidium sativum's antioxidant, anti-inflammatory, antibacterial, and tissue-regenerative qualities show promise for wound healing.⁷⁹ Flavonoids, phenolic compounds, alkaloids, and glucosinolates are among its bioactive components that promote angiogenesis, fibroblast proliferation, collagen synthesis, and re-epithelialization.⁷ While Lepidium sativum's anti-inflammatory properties reduce inflammatory mediators involved in tissue regeneration, its antioxidant activity supports decreasing oxidative stress at the wound site.7, 12, 26 Sahane et al.⁵⁹ studied ethanolic Lepidium sativum seed extract in an STZ-induced diabetic rat excision wound model. Oral (20 and 30 mg/kg) and topical treatments enhanced wound closure, increased hydroxyproline and hexosamine content, and reduced wound area and clotting time. The extract also lowered blood glucose and improved red blood cell count, white blood cell count, and total protein levels. Increased hydroxyproline and hexosamine indicated enhanced collagen synthesis and extracellular matrix formation. The wound healing activity was attributed to antihyperglycemic, antioxidant, and anti-inflammatory effects. The study provided preliminary evidence using oral and topical formulations and multiple biochemical markers; however, animal-only evidence, lack of clinical validation, and limited molecular pathway analysis remain limitations.

5.10.2. Osteoprotective activity

Lepidium sativum demonstrates osteoprotective potential through bioactive compounds, including flavonoids, alkaloids, phenolic compounds, glucosinolates, and minerals like calcium, phosphorus, and iron.¹² These compounds may promote bone health by increasing osteoblast activity, enhancing bone matrix, and facilitating mineralization. Lepidium sativum regulates osteogenic markers and suppresses excessive osteoclast-mediated bone resorption, among other processes involved in bone remodeling.³ Additionally, its anti-inflammatory and antioxidant properties can help prevent oxidative stress and inflammatory processes that hasten bone loss.12, 33 Abdallah et al.³³ evaluated the extract of Lepidium sativum in ovariectomized rats at 50 and 100 mg/kg vs. 17β-estradiol. UHPLC/PDA/ESI–MS and SPME-GC/MS identified glucosinolates, lignans, coumarins, phenolic acids, and alkaloids. The extract prevented bone loss by enhancing bone weight, femoral strength, osteocalcin, and lactate dehydrogenase (LDH), preserving SOD and GPx, reducing lipid peroxidation, decreasing CTX-I and TRAP, and regulating the RANKL/OPG pathway. The study showed strong biochemical, mechanical, and metabolomic evidence. However, the animal model limits direct translation to humans, requiring clinical validation and long-term safety studies.

El-Haroun et al.⁶⁰ compared Lepidium sativum (300 mg/kg) with teriparatide (4 μg/kg) in 60 adult male guinea pigs divided into 6 groups with glucocorticoid-induced osteoporosis. Lepidium sativum improved cortical and trabecular changes, reduced resorption cavities, collagen loss, osteoclast activity, and osteocyte apoptosis, increased osteoblast-related changes, and improved serum calcium and alkaline phosphatase alterations. It showed greater protective efficacy than teriparatide. However, limited mechanistic, pharmacokinetic, and clinical evidence restricts its clinical relevance.

5.11. Reproductive and women's health activities and fertility-enhancing activity

Lepidium sativum has long been known to have advantages for reproductive health. Its bioactive components, flavonoids, alkaloids, phytosterols, polyphenols, and minerals that may enhance reproductive function, are primarily responsible for its fertility-enhancing properties.⁷⁵ It has been linked to changes in reproductive parameters through antioxidant defense, regulation of hormonal balance, improved gonadal function, and protection of reproductive organs from oxidative damage.² Its phytochemicals may enhance sperm quality by lowering lipid peroxidation and promoting spermatogenesis. Its estrogenic properties and nutritional components may assist female reproductive health.⁸⁰ Furthermore, Lepidium sativum may influence reproductive signaling pathways associated with tissue integrity, endocrine control, and gamete development, suggesting its potential as a natural fertility-supporting agent.⁶¹

Moustafa et al.⁶¹ evaluated LSSE in letrozole (1 mg/kg) and HFD-induced PCOS rats. Sixty rats were divided into five groups (n = 12): control, polycystic ovary syndrome (PCOS), PCOS + LSSE (250 mg/kg), PCOS + LSSE (500 mg/kg), and metformin (200 mg/kg) for 4 weeks. LSSE improved metabolic, hormonal, antioxidant, inflammatory, fertility, pregnancy, and histological outcomes. The 500 mg/kg dose showed better biochemical effects, while 250 mg/kg produced better pregnancy outcomes. The study shows a validated PCOS model, dose comparison, metformin as a reference treatment, and assessment of multiple outcomes. However, translation to humans remains limited due to species differences, uncertain equivalent human dosing, and insufficient long-term safety evidence. Ibraheem et al.⁶² investigated the aqueous extract of Lepidium sativum in male mice. Forty-eight mice were divided into four groups (n = 12): control, Lepidium sativu extract, sulpiride-induced hyperprolactinemia, and sulpiride + LS extract. LS extract enhanced reproductive function by increasing follicle-stimulating hormone (FSH) and testosterone concentrations, reducing prolactin levels, and improving sperm-related fertility outcomes in male mice. Hyperprolactinemic mice showed reduced sperm count (53.33 ± 1.76 sperm/ml), motility (33.33 ± 3.33%), and viability (46.67 ± 1.67%). The study supports reproductive effects through hormonal regulation and testicular protection. However, the induced animal model and lack of phytochemical standardization limit the generalizability and clinical applicability of these findings.

5.12. Bronchodilatory and anti-asthmatic activity

Lepidium sativum has shown antiasthmatic properties due to its bioactive compounds, including flavonoids, alkaloids, phenolic compounds, and glucosinolates.⁷ Its anti-asthmatic effects are linked to improved bronchial relaxation, decreased oxidative stress, and regulation of airway inflammation. Lepidium sativum may improve respiratory function by reducing mucus production, promoting smooth muscle relaxation, and inhibiting inflammatory mediators linked to airway hyperresponsiveness.4, 5 Furthermore, its antioxidant activity may protect airway tissues from oxidative damage, which is crucial to the development and course of asthma.⁶ Rehman et al.4, 5 evaluated the bronchodilatory mechanism of Lepidium sativum crude extract using isolated guinea pig tracheal preparations. Lepidium sativum crude extract inhibited carbachol (1 μM) and K⁺ (80 mM) contractions. At 0.03 mg/mL, it showed anticholinergic activity, while 0.1 mg/mL reduced the maximum response. Lepidium sativum crude extract (0.1–0.3 mg/mL) demonstrated Ca²⁺ channel blocking activity similar to verapamil, and 0.03–0.1 mg/mL enhanced isoprenaline relaxation, suggesting Phosphodiesterase inhibition (PDE) inhibition. The bronchodilatory effect involved anticholinergic, Ca²⁺ antagonist, and PDE inhibitory pathways. However, the isolated tissue model limits clinical translation, and further in vivo.

Paranjape and Mehta⁶³ assessed the efficacy and safety of Lepidium sativum seeds in 30 patients with mild-to-moderate bronchial asthma. Patients received L. sativum seed powder 1 g three times daily for 4 weeks. Significant improvements were observed in FVC, FEV₁, FEF25–75%, and MVV, clinical symptoms, and asthma severity, with no adverse effects reported. However, small sample size, short duration, and lack of placebo control limit the reliability and generalizability of findings.

5.13. Other pharmacological activities of Lepidium Sativum

Lepidium sativum also exhibits several additional pharmacological activities beyond those discussed above. These include antipyretic,¹⁰ antiviral, anthelmintic, apoptosis-inducing, antihyperlipidemic, anti-obesity,⁶ vasoprotective,⁸¹ gastroprotective,¹⁰ and antiurolithiatic⁸² effects. It also shows potential memory-enhancing,⁸³ anxiolytic,⁴⁴ bone-regenerative,⁸⁴ galactagogue,³ reproductive protective,⁶ antitussive,⁸⁵ and hematopoietic⁶⁶ activities. Furthermore, its dermatological protective effects, including skin wound healing, dermal protection, and anti-aging activity, highlight its therapeutic versatility.⁸⁶ However, these emerging activities require further mechanistic investigations and clinical validation to confirm their therapeutic significance.

6. Phytochemical characterization and standardization of Lepidium sativum extracts

Although various Lepidium sativum preparations, including aqueous, ethanolic, methanolic, chloroform, seed oil, and nanoparticle-based extracts, have demonstrated pharmacological activities, differences in extraction procedures and phytochemical profiles may contribute to variability among reported findings.⁶⁸ Therefore, standardized extraction methods, defined chemical markers, and validated analytical approaches are essential to ensure reproducibility and quality control.⁸⁷ Recent phytochemical investigations have advanced the characterization of bioactive constituents in Lepidium sativum.¹²,88, 89identified 12 flavonoid glycosides, including 5 new compounds (lepisativutmines Q–U), from L. sativum seeds using high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR) spectroscopy, and tandem mass spectrometry (MS/MS), and sugar configuration analysis. Several compounds showed protein tyrosine phosphatase 1B (PTP1B) inhibition (IC₅₀ = 60.58 ± 3.53 and 33.90 ± 2.89 μM), α-glucosidase inhibition (IC₅₀ = 25.96 ± 0.30 μM), and weak nitric oxide inhibition (IC₅₀ = 92.28 ± 4.19 and 40.77 ± 1.50 μM). These findings provide potential chemical markers for L. sativum standardization; however, their effects on crude extracts, bioavailability, and clinical relevance require further validation.

Additionally,88, 89identified 4 new and 4 known compounds from L. sativum seeds. Compound (+)-1 showed moderate HeLa cell inhibition (IC₅₀ = 19.99 ± 1.00 μM), while compound (−)-1 showed weak activity (IC₅₀ = 60.23 ± 3.51 μM). These results improve understanding of L. sativum bioactive constituents, but further studies are needed for extract standardization and therapeutic confirmation. These findings indicate that the pharmacological effects of Lepidium sativum are associated with specific phytochemical constituents rather than crude extracts alone. Therefore, future studies should incorporate standardized extraction procedures, quantification of marker compounds, validated quality-control parameters, and assessment of batch-to-batch consistency. Such approaches will improve reproducibility, facilitate comparison between studies, and support the translation of experimental findings into evidence-based therapeutic applications.

7. Distinction between experimental evidence and clinical applications

Most pharmacological activities of Lepidium sativum have been demonstrated through in vitro and animal studies, with limited clinical evaluation. Preclinical evidence supports antioxidant,24, 26 anti-inflammatory,28, 29 antimicrobial,34, 36 anticancer,38, 39, 40 antidiabetic,27, 42, 45 gastroprotective,49, 50 hepatoprotective,⁵³ nephroprotective,54, 55 neuroprotective,57, 58 osteoprotective,33, 60 wound-healing,⁵⁹ and reproductive protective⁶² effects.

These activities are associated with enhanced antioxidant defense, inhibition of inflammatory pathways such as NF-κB, TNF-α, and IL-6, and regulation of apoptotic pathways involving BAX, BCL2, and caspase-3. Other reported mechanisms include modulation of the RANKL/OPG pathway, α-glucosidase inhibition, muscarinic receptor antagonism, calcium-channel blockade, phosphodiesterase inhibition, and p53-mediated apoptosis. Importantly, these findings represent experimentally demonstrated biological effects and should be distinguished from clinically validated therapeutic applications. Most available evidence demonstrates biological activity under preclinical conditions, but the translation of these effects into clinical benefits in humans remains uncertain.

Clinical evidence for L. sativum remains limited. The main human study identified was the clinical trial by Paranjape and Mehta.⁶³ This study reported improvements in pulmonary function and asthma symptoms following L. sativum seed administration in patients with mild-to-moderate bronchial asthma. However, the study was limited by its small sample size, short treatment duration, and lack of a placebo-controlled design. Therefore, although preclinical studies demonstrate promising biological activity, these findings should not be equated with clinically validated therapeutic effects. Further well-designed clinical trials using standardized extracts, adequate sample sizes, optimized doses, pharmacokinetic evaluation, and long-term safety assessment are required before these effects can be considered clinically validated therapeutic applications.

8. Toxicological and safety studies of Lepidium sativum

Lepidium sativum is generally considered safe when consumed at traditional dietary and therapeutic doses and exhibits a favorable safety profile⁶ (Table 5). It has low toxicity and is well tolerated after single-dose administration at tested doses.⁷³ However, excessive or prolonged use may cause adverse effects due to its bioactive constituents, particularly glucosinolates and their hydrolysis products, which may interfere with thyroid function and pose potential reproductive risks.⁹⁰ In addition, variability in phytochemical composition, dosage, and preparation methods may influence its safety.¹² Therefore, standardized formulations, comprehensive toxicological evaluation, and well-designed clinical studies are needed to establish its long-term safety and therapeutic applicability.³,⁹⁰ evaluated the acute and subacute oral toxicity of the 70% ethanol extract of Lepidium sativum seeds in Wistar rats. Acute toxicity showed no mortality up to 5000 mg/kg, with an oral median lethal dose (LD₅₀) > 5000 mg/kg, classifying it as practically non-toxic (Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Category 5). However, 28-day administration of 500 and 1000 mg/kg caused dose-dependent toxicity, including diarrhea, reduced movement, piloerection, hepatic enlargement, elevated liver enzymes, altered hematological parameters, and liver histopathological changes, suggesting potential hepatotoxicity at higher doses.

Table 5.

Toxicological and safety studies.

Study design	Model	Extract/Formulation	Dose	Duration	Major findings	Critical appraisal	References
Acute and subacute toxicity study	Wistar rats	70% ethanol seed extract	Up to 5000 mg/kg acute; 500 and 1000 mg/kg subacute	14 and 28 days	LD₅₀ >5000 mg/kg; high doses caused hepatic enlargement, enzyme elevation, and histological changes.	Strong safety evaluation; long-term human safety remains unknown.	Aragie et al.90
Acute and subacute toxicity study	Wistar rats	Seed fixed oil	LD₅₀ 2818.32 mg/kg	14 and 28 days	Caused behavioral changes, biochemical alterations, and hematological disturbances.	Highlights formulation-dependent toxicity.	Aragie et al.91

⁹¹ also assessed the toxicity of Lepidium sativum seed fixed oil in Wistar albino rats. The oil showed an oral LD₅₀ of 2818.32 mg/kg, classified as slightly hazardous according to World Health Organization (WHO). 28-day repeated administration caused piloerection, lethargy, tremors, changes in body weight, organ pathology, hematological indices, and biochemical parameters, indicating toxicity with prolonged exposure. Compared with the ethanolic extract, the fixed oil showed greater toxicity in the formulation-specific safety assessment.

9. Limitations of the review

Several limitations should be considered. First, this narrative review does not include quantitative data pooling or meta-analysis; therefore, effect sizes and the strength of evidence for reported pharmacological activities cannot be statistically evaluated. Second, substantial heterogeneity exists among available studies regarding plant parts, geographical origin, cultivation conditions, extraction methods, phytochemical composition, experimental models, and assessment protocols, which may limit comparability and interpretation of findings. Additionally, most reported effects are based on in vitro and in vivo studies, while well-designed clinical studies remain limited, highlighting the need for standardized clinical validation before practical application. Variations in phytochemical profiles, environmental factors, and preparation methods may also affect the reproducibility and therapeutic consistency of Lepidium sativum-derived products. Furthermore, publication bias may be present because studies showing positive pharmacological outcomes are more likely to be published. Important gaps remain regarding pharmacokinetics, bioavailability, molecular targets, long-term safety, toxicity, and potential herb–drug interactions, requiring further comprehensive investigations.

10. Future directions

To translate Lepidium sativum L. from traditional medicine into evidence-based therapeutic applications, several research gaps must be addressed despite its extensive traditional use and increasing scientific evidence. Future studies should focus on standardized phytochemical characterization using advanced analytical platforms, including metabolomics, HPLC, LC–MS, and NMR spectroscopy, to establish comprehensive chemical profiles and identify therapeutically important bioactive compounds. Further investigation is required to elucidate the molecular mechanisms and biological targets underlying its pharmacological effects, particularly pathways related to oxidative stress regulation, inflammation, metabolic homeostasis, immune modulation, and tissue protection.

Future research should also prioritize the standardized formulations and advanced delivery systems, including nanoencapsulation, phytosomes, and targeted nanotechnology-based approaches, to enhance bioavailability, stability, and therapeutic efficacy. Comprehensive pharmacokinetic and pharmacodynamic studies are needed to evaluate absorption, distribution, metabolism, elimination, bioavailability, and dose–response relationships. Interdisciplinary collaboration among ethnobotany, phytochemistry, pharmacology, molecular biology, nutrition science, and clinical medicine will be essential for developing standardized extracts, functional foods, nutraceuticals, and plant-derived medicines. Ultimately, the clinical establishment of Lepidium sativum as a validated medicinal resource requires rigorous evaluation of its bioactive compounds, mechanisms of action, pharmacokinetic properties, safety profiles, and clinical efficacy.

11. Conclusion

Lepidium sativum exhibits diverse pharmacological activities, including antioxidant, anti-inflammatory, analgesic, antimicrobial, antidiabetic, gastroprotective, hepatoprotective, nephroprotective, cardioprotective, neuroprotective, osteoprotective, wound-healing, reproductive, and anticancer effects. These activities are mainly attributed to its bioactive constituents, including glucosinolates, alkaloids, phenolics, flavonoids, coumarins, and lignans. Preclinical studies provide substantial evidence from multiple experimental models and demonstrate regulation of oxidative stress, inflammation, apoptosis, metabolic pathways, and cellular signaling mechanisms. However, clinical evidence remains limited. Although generally safe at traditional doses, high-dose or prolonged use of concentrated preparations may cause toxicity. Therefore, further pharmacokinetic studies, standardized formulations, comprehensive safety evaluations, and well-designed clinical trials are required to confirm its therapeutic efficacy and clinical applicability.

Declaration of generative AI in scientific writing

During the preparation of this work, the author used ChatGPT5 only to improve readability and language. After using this tool/service, the author reviewed and edited the content as needed and took full responsibility for the published article.

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CRediT authorship contribution statement

Gudisa Bereda: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

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Declaration of competing interest

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

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