Plant iridoids: Chemistry, dietary sources and potential health benefits

Abstract

Iridoids, a diverse class of plant food monoterpenoids, are characterized by a cyclopentane-fused pyran ring structure and exhibit extensive structural diversity and functional versatility. This review highlights recent advances in iridoid chemistry, biosynthesis via the methylerythritol phosphate pathway, and advanced extraction techniques such as ultrasound-assisted, microwave-assisted, and supercritical fluid extraction. Analytical methods such as liquid chromatography-mass spectrometry enable precise identification and quantification, advancing the study of their health-promoting properties. Iridoids demonstrate potent antioxidant, anti-inflammatory, neuroprotective, antitumor, antiviral, and hepatoprotective effects suggesting their potential use in functional foods, nutraceuticals, pharmaceuticals, and cosmetics. However, for the successful commercialization of iridoid-based products, future research should aim at the cost-effective production of iridoids using sustainable production systems, biotechnological synthesis, and clinical validation. This review reveals the significant promise of iridoids in enhancing human health through potential product innovation and assessment.

Highlights

• •Iridoids exhibit antioxidant, anti-inflammatory, and neuroprotective activities.
• •Advanced sustainable extraction techniques improve iridoid recovery.
• •Iridoids regulate lipid metabolism and enhance insulin sensitivity.
• •Industrial applications face challenges in cost, stability, and regulation.

1. Introduction

Iridoids are a class of plant food bioactive constituents, classified as heterocyclic monoterpenoids with a characteristic cyclopentane-fused pyran ring structure. The cyclopentane ring forms the core skeletal framework of iridoids. Cleavage of the ring structure and modifications lead to various iridoid derivatives. Iridoids predominantly exist as 1-O-glucosides, where a glucose moiety is attached to the C-1 position of the pyran ring (Dinda, Debnath, & Harigaya, 2007; Przybylska, Kucharska, & Sozański, 2023). These compounds play critical roles in plant physiology and defense mechanisms. They contribute to both biotic and abiotic stress responses. Iridoids are widespread across various plant families, particularly in dicotyledonous plants from the Scrophulariaceae, Pyrolaceae, Oleaceae, Lamiaceae, Rubiaceae, Caprifoliaceae, and Gentianaceae families. The distribution features their evolutionary significance in plant survival and adaptation (Hernández Lozada et al., 2022; Kucharska, 2017; Liu et al., 2021; Wang et al., 2020). The plant sources of iridoids serve as an integral part of traditional diets and remedies and provide a foundation for developing novel functional foods. Despite their abundance in nature, research into optimizing iridoid extraction and analysis has only recently advanced, utilizing emerging technologies such as ultrasound-assisted extraction, enzymatic hydrolysis, and high-performance liquid chromatography-mass spectrometry (HPLC-MS) for their characterization and quantification (Dadan, Grobelna, Kalisz, & Witrowa-Rajchert, 2022).

With the increasing global interest in natural and health-enhancing food bioactives, iridoids are emerging as promising candidates for developing functional foods and nutraceuticals. Compared to other well-studied phytochemicals such as polyphenols and carotenoids, iridoids remain underexplored in terms of their chemical diversity, dietary sources, and mechanisms of action. However, their structural uniqueness and bioactivity suggest significant potential in modulating metabolic and immune functions (Deng, West, Palu, & Jensen, 2011; Kucharska, 2017; Kucharska & Fecka, 2016; Neupane, Adhikari Subin, & Adhikari, 2024). In recent years, iridoids have drawn considerable interest due to their potential health benefits. Iridoids possess antioxidant properties, play essential roles in protecting cells from viral and bacterial infections, and assist in the rapid regeneration of injured tissues. Furthermore, iridoid glycosides sourced from various medicinal plants have demonstrated therapeutic value in managing neurological diseases, diabetes, cardiovascular conditions, and various cancers (Chan et al., 2020; Kim & Choi, 2021; Kucharska, Sokół-Łętowska, Oszmiański, Piórecki, & Fecka, 2017; Marchetti et al., 2024; Przybylska et al., 2023; Tenuta et al., 2020; Wang, Gong, et al., 2020). Iridoids possess considerable potential for industrial utilization in the food, pharmaceutical, and cosmetic industries due to their bioactive and multifunctional characteristics. For instance, the integration of iridoids into functional beverages, nutraceutical and nutritional supplements, and personal care formulations reveals emerging innovations. Additionally, the abundance of iridoids in edible sources such as fruits, vegetables, and medicinal herbs signifies their safety and applications in supplemented food and dietary supplements (Danielewski, Matuszewska, Nowak, Kucharska, & Sozański, 2020; Przybylska, Kucharska, Piórecki, & Sozański, 2024; Tang et al., 2021).

This review aims to provide a comprehensive knowledge of plant iridoids, focusing on their chemistry, biosynthesis, extraction, dietary sources, health benefits, and industrial applications. By reviewing current knowledge and identifying research gaps, this article advances understanding of iridoids and attempts to inspire further exploration into their applications in supplemented food, nutraceutical, pharmaceutical, and cosmetic product development.

2. Chemistry of iridoids

Iridoids are gaining increasing attention in the food industry owing to their distinctive chemical structures and broad spectrum of biological activities (Tang et al., 2021). A comprehensive understanding of their functional roles in food systems requires an in-depth examination of their molecular characteristics. This encompasses not only their core cyclopentanopyran scaffold but also the diversity of substituent groups and stereoisomeric forms that affect their physicochemical properties and biological functions related to human health. The following sections provide a systematic overview of the structural features, molecular diversity, functional attributes, and structure–activity relationships that support the application of iridoids in functional foods and dietary supplements.

2.1. Basic chemical structure

Iridoids are natural compounds characterized by a core structure known as cyclopentanopyran, which consists of cis- or trans-fused cyclopentane and oxygen-containing heterocyclic rings (Dinda et al., 2007; Ndongwe et al., 2023). The primary types of iridoids include glycosidic iridoids, non-glycosidic iridoids, secoiridoids, and bis-secoiridoids (also known as dimer iridoids) (Fig. 1), which vary due to differences in their biosynthetic pathways (Boros & Stermitz, 1990; Boros and Stermitz, 1991, El-Naggar and Beal, 1980; Frezza, Venditti, De Vita, Guiso, & Bianco, 2024; Frezza, Venditti, De Vita, Guiso, & Bianco, 2025; Wang, Gong, et al., 2020).

Fig. 1.

Basic structures and major derivatives of plant food iridoids (glycosides and non-glycosides).

2.2. Structure diversity and substituent variability

Iridoids exhibit considerable structural diversity, which is primarily attributed to the enzymatic modifications of their core cyclopentanopyran scaffold. These modifications introduce a wide range of substituent groups, including hydroxyl, methyl, glycosyl, and acyl groups, each impacting the chemical characteristics and biological functions of iridoids (Liu et al., 2024; Wang et al., 2024; Zhang, Wu, Liu, Chen, & Li, 2023). The variability in the type and position of these substituents contributes to the complexity of iridoid structures, leading to a broad spectrum of bioactive properties. Furthermore, iridoids commonly occur as stereoisomers, including cis-trans isomers, enantiomers, and diastereomers. These isomeric forms are primarily generated through stereoselective enzymatic reactions during iridoid biosynthesis. Enzymes such as iridoid synthases and reductases catalyze key steps that determine the configuration of the fused rings and the stereochemistry of substituents. The specific orientation of these centers is influenced by the enzyme's active site architecture, as well as reaction conditions, including temperature, pH, and substrate availability (Hernández Lozada et al., 2022; Kucharska & Fecka, 2016; Mao, Chou, Zhao, & Zhang, 2016). Species-specific gene expression further contributes to isomer diversity, as different plants may express different sets or isoforms of biosynthetic enzymes. These stereoisomers often exhibit distinct physicochemical and biological properties (Aničić et al., 2024). Such structural and substituent variability plays a critical role in determining the potential applications of iridoids in functional foods, nutraceuticals, and drug discovery (Przybylska et al., 2023; Wang, Gong, et al., 2020).

2.3. Physicochemical properties

The physicochemical characteristics of plant iridoids, such as solubility and thermal stability, pH sensitivity, and molecular polarity, are pivotal in determining their functionality, bioavailability, and industrial applications (Chen et al., 2024; Hussain, Green, Saleem, Raza, & Nazir, 2019). Structurally, iridoids often occur as glycosides or aglycones, with the glycosylated forms displaying higher water solubility due to the presence of polar sugar moieties (Luca, Miron, Ignatova, & Skalicka-Woźniak, 2019; Neri, Angolini, Bicas, Ruiz, & Pastore, 2018; Singh, Kumar, Dwivedi, Yadav, & Sharma, 2023). This property makes glycosides particularly suitable for use in aqueous formulations such as beverages, syrups, or emulsions (Luca et al., 2019; Neri et al., 2018). In contrast, the aglycone forms, characterized by reduced polarity, exhibit greater lipophilicity, rendering them ideal for lipid-based food matrices or encapsulated nutraceutical products. Iridoids exhibit high sensitivity to environmental conditions, such as temperature and pH. Under acidic or high-temperature processing conditions, glycosidic bonds are susceptible to hydrolysis, which can lead to the degradation of the iridoid structure, therefore, a reduction in their bioactivity. Geniposidic acid was found to be highly stable across all tested environments. In contrast, scyphiphin D, ulmoidoside A, and ulmoidoside C showed moderate stability and were only degraded under strong alkaline conditions. Ulmoidoside B and ulmoidoside D were more sensitive and degraded under elevated temperature, acidic, and alkaline conditions. These results demonstrate that the environmental sensitivity of iridoids depends on their chemical structure, with some compounds being more prone to degradation than others (Kouda & Yakushiji, 2020; Ma et al., 2022). During iridoid extraction, carboxyl groups in their structures may undergo esterification with ethanol, resulting in the formation of artifact-derived compounds such as oleoside 7-ethyl 11-methyl ester (Venditti, 2020). Moreover, the presence of functional groups, including hydroxyl, carboxyl, and methoxy groups, not only controls their chemical reactivity but also impacts their association with other food elements, such as proteins, lipids, and polyphenols. These interactions may enhance or inhibit the antioxidant activity of iridoids, depending on the food matrix (Kong et al., 2023; Kong, Yang, Zhang, & Dong, 2022; Shao et al., 2018). Additionally, their molecular mass and polarity impact their gastrointestinal absorption and transport, directly affecting their bioavailability and health-promoting potential. A comprehensive understanding of these physicochemical properties is essential for the effective design of functional foods and nutraceuticals that preserve the bioactivity, stability, and efficacy of plant iridoids during production, storage, and digestion (Arraché Gonçalves, Eifler-Lima, & von Poser, 2022; Danielewski et al., 2020; Sun et al., 2021).

2.4. Structure-Activity Relationship (SAR)

The SAR of plant iridoids emphasizes the critical role of their chemical structures in determining biological functions and health benefits (Saidi et al., 2020; Tundis, Loizzo, Menichini, Statti, & Menichini, 2008). Key structural features, such as the cyclopentanopyran ring system, functional group substitutions, and glycosylation patterns, significantly influence their antioxidant, anti-inflammatory, and antimicrobial activities. Lipophilic substitutions, such as methyl or acyl groups, can increase membrane permeability, enhancing the bioaccessibility of aglycones in lipid environments (Kharb et al., 2022; Kouda & Yakushiji, 2020; Wang, Zheng, et al., 2024). Additionally, variations in the position and type of substituents, such as carboxyl or methoxy groups, can modulate binding affinities to biological targets, influencing anti-inflammatory and antimicrobial efficacy (Hernández Lozada et al., 2022; Imadzu, Sugimoto, Matsunami, & Otsuka, 2018). These SAR insights are crucial for understanding the functional properties of iridoids and optimizing their use in functional foods and nutraceuticals.

3. Biosynthesis of iridoids

The biosynthesis of iridoids is a highly complex and regulated process, influenced by a number of genetic and environmental factors. This section explores the underlying genetic mechanisms and the biosynthetic pathways that lead to the production of iridoids in plants, focusing particularly on key enzymes, regulatory networks, and the plant-specific variations observed in different species.

3.1. Genetic regulation

The biosynthesis of iridoids primarily occurs through the methylerythritol phosphate (MEP) pathway in plastids, generating geranyl pyrophosphate as a precursor (Fig. 2) (Sampaio-Santos & Kaplan, 2001). At the C-8 position, two distinct epimers are formed, each resulting from different biosynthetic pathways. Route I typically produces compounds with 8β-stereochemistry, while Route II leads to compounds with 8α-stereochemistry (Jensen, 1991). The biosynthesis of iridoids is intricately controlled by a network of transcription factors and genes (Palmer, 2021; Wang et al., 2024). Myeloblastosis (MYB) and WRKY transcription factors are implicated in the upregulation of key enzymes such as iridoid synthase and geraniol 8-hydroxylase (Sui, 2017; Wang, Geng, et al., 2024; Yin et al., 2024). Advances in transcriptomics and CRISPR/Cas9-based genome editing have uncovered candidate genes modulating iridoid biosynthesis in response to specific environmental stimuli, including light intensity and nutrient availability (Das, Kwon, & Kim, 2024). The biosynthesis of iridoids originates from geranyl diphosphate, undergoing enzymatic transformations involving hydroxylation, oxidation, and cyclization (Kouda & Yakushiji, 2020). These pathways highlight the complex enzymatic networks required for iridoid biosynthesis, providing insights into their structural diversity and biological functions (Fig. 2). Understanding these regulatory mechanisms enables precise control of iridoid biosynthesis in plants as well as using chassis organisms in metabolic engineering and synthetic biology applications (Hernández Lozada et al., 2022).

Fig. 2.

Biosynthetic pathway of iridoids in plants.

3.2. Plant-specific variations

Iridoid biosynthesis varies significantly across plant species, reflecting evolutionary adaptations and ecological pressures (Larsen et al., 2017; Munkert et al., 2015). For instance, the relative abundance of specific iridoids in Lonicera caerulea (blue honeysuckle or haskap berries) differs from that in Plantago lanceolata (English plantain), due to variations in enzyme isoforms and substrate specificity (Aničić & Mišić, 2024; Budzianowska & Budzianowski, 2022; Kumar, Chauhan, & Tandon, 2017; Marak, Biere, & Van Damme, 2000; Zhang, Zheng, Wang, Ni, & Wang, 2020). Notably, many endemic or region-specific species exhibit distinct iridoid profiles. For instance, Vinca sardoa contains loganic acid and loganin, whereas Euphrasia genargentea accumulates aucubin, catalpol, mussaeenosidic acid, and melampyrosides. Linaria arcusangeli produces linaride, antirrhide, arcusangeloside, and 5-deoxyantirrhoinoside, highlighting the structural diversity within the same genus (Bianco, Serrilli, Venditti, Petitto, & Serafini, 2016). Furthermore, certain plants possess unique iridoid profiles influenced by environmental factors through iridoid biosynthetic pathways (De Luca, Salim, Thamm, Masada, & Yu, 2014; Ye et al., 2019). Comparative metabolomics and evolutionary studies are pivotal in identifying plant-specific traits and facilitating the breeding and selection of iridoid-rich cultivars for diverse dietary and therapeutic applications.

4. Extraction and analysis of iridoids

Due to the structural diversity and varying chemical properties of iridoids, effective extraction methods are critical for obtaining these compounds with high purity and yield. This section reviews advanced extraction techniques, purification processes, and analytical methods employed to identify and quantify iridoids, with a focus on recent developments in the field.

4.1. Extraction techniques

Advanced extraction methods, such as ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE), and supercritical fluid extraction (SFE), offer improved efficiency and reduced environmental impact (Valisakkagari, Chaturvedi, & Rupasinghe, 2024). Merging extraction strategies has shown promise in enhancing the recovery of iridoid compounds. For instance, an integrated method combining choline–tryptophan ionic liquid-based aqueous biphasic systems enabled the selective extraction of aucubin from Eucommia ulmoides leaves. The process resulted in the formation of a viscous interfacial phase in which aucubin was concentrated up to 15 %, highlighting the system's strong selectivity and efficiency in isolating iridoids from complex plant matrices. Similarly, the ultrasonic–microwave synergistic extraction (UMSE) technique was employed to extract total iridoid glycosides from Patrinia scabra, yielding 81.4 mg/g under optimized conditions. Subsequent fractionation using 30 % and 50 % ethanol eluents further enriched the iridoid glycosides to 498 and 507 mg/g, respectively (Ma et al., 2022; Náthia-Neves, Tarone, Tosi, Júnior, & Meireles, 2017; Siddiqui, Ali Redha, Salauddin, Harahap, & Rupasinghe, 2025; Wang, Yang, Lv, Tan, & Zhang, 2022). Ultrasound-assisted extraction (UAE) employs ultrasonic waves to disrupt plant cell walls, thereby facilitating the release of iridoids into the solvent. In contrast, microwave-assisted extraction (MAE) utilizes microwave energy to rapidly heat the solvent and plant matrix, enhancing mass transfer and extraction efficiency. For example, UAE combined with natural deep eutectic solvents (NADES) was applied to STF231, a medicinal plant by-product, for iridoid recovery. Under optimized conditions, gentiopicroside was successfully identified, indicating high extraction efficiency and notable antioxidant activity. Similarly, MAE was used to extract iridoid glycosides such as ajugol and catalpol from Radix rehmanniae. The method demonstrated high extraction performance, with recovery rates ranging from 93.8 % to 106 % and relative standard deviations below 5.0 %, underscoring its reliability and reproducibility (Marchetti et al., 2024; Wang et al., 2020). Supercritical fluid extraction (SFE), utilizing supercritical CO₂ as a solvent, is particularly advantageous due to its environmental sustainability and ability to preserve thermolabile iridoids. For instance, the combination of SFE with Separation Box (Sepbox; combination of HPLC and solid phase extraction) technology was employed to isolate the iridoid lactone plumericin from Momordica charantia vine. This method achieved a relatively high yield and demonstrated potent bioactivity (Saengsai, Kongtunjanphuk, Yoswatthana, Kummalue, & Jiratchariyakul, 2015; Tang et al., 2021). Optimizing extraction parameters, such as solvent type, temperature, time, and solid-to-solvent ratio, is crucial for maximizing iridoid yields. Response Surface Methodology (RSM) has been applied to determine optimal extraction conditions for various phytochemicals, including iridoid glycosides. For instance, in the extraction of iridoids from Patrinia scabra, RSM optimization identified the following conditions: 52 % ethanol concentration, a material-to-solvent ratio of 1:18 (g/mL), microwave power of 610 W, and an extraction time of 50 min. Under these conditions, the yield of total iridoid glycosides reached 81.4 mg/g. These findings underscore the effectiveness of RSM in optimizing extraction parameters and significantly enhancing iridoid glycoside yields (Ma, Lu, et al., 2022; Valisakkagari & Rupasinghe, 2025).

4.2. Purification

Purification of iridoids is a crucial step in characterizing their bioactivity and assessing pharmacological applications. Crude extracts obtained from the extraction process typically contain a complex mixture of iridoids, flavonoids, phenolic acids, and other phytochemicals (Kucharska et al., 2017; Zhang et al., 2022). Venditti et al. (2012) utilized a combination of adsorption onto a charcoal/celite/polyamide mixture and gradient elution with water and aqueous ethanol, followed by purification via silica gel column chromatography. This method enabled the efficient isolation of several iridoid glycosides from Plantago sempervirens, including aucubin, plantarenaloside, bartsioside, gardoside, caryoptoside, 8-epiloganic acid. Applying the same technique, iridoid compounds such as agnuside, adoxosidic acid, and monotropein were also successfully extracted from Odontites luteus. Overall, this extraction strategy proved effective for recovering a wide range of iridoid glycosides (Ballero, Bianco, & Serrilli, 2009; Venditti et al., 2012; Venditti et al., 2017). Liquid-liquid partitioning is often the first step in separating iridoids based on their polarity, using solvents such as ethanol, methanol, ethyl acetate or water. Liquid-liquid extraction using 80 % methanol acidified with 1 % hydrochloric acid has proven to be an effective method for isolating iridoids from Lonicera caerulea berries, facilitating the purification of compounds such as loganic acid, 7-epiloganic acid, and secologanin (Kucharska, 2017; Kucharska & Fecka, 2016; Luca et al., 2019; Yu et al., 2020). Refined purification approaches, including column chromatography, preparative high-performance liquid chromatography (prep-HPLC), and counter-current chromatography (CCC), are broadly applied. For instance, Premna fulva leaves were processed using high-speed counter-current chromatography (HSCCC) and prep-HPLC to effectively isolate three new iridoid glycosides: 6-O-((2″-(3″′-O-trans-p-methoxycinnamoyl)-α-L-rhamnopyranosyl)-(3″-O-trans-p-methoxycinnamoyl)) α-L-rhamnopyranosyl catalpol, 6-O-(2″,4″-di-trans-p-methoxycinnamoyl)-α-L-rhamnopyranosyl, and 6-O-(3″-O-trans-m-methoxycinnamoyl)-α-L-rhamnopyranosyl catalpol (He et al., 2023; Wang et al., 2015). Column chromatography, utilizing stationary phases such as silica gel or Sephadex, enables efficient separation of compounds based on molecular size and polarity. Prep-HPLC provides high resolution and is particularly effective for isolating individual iridoids from complex mixtures (Lu et al., 2016). The CCC, a solvent-based partitioning technique, is advantageous due to its high recovery rates and capacity to process large sample volumes. For instance, Gentianae radix was used as the starting material, and HSCCC was employed to purify loganic acid, swertiamarin, gentiopicroside, and trifloroside. These iridoid and secoiridoid glycosides were obtained with high purity, demonstrating the efficacy of HSCCC in isolating bioactive compounds (Chen, Peng, Wang, Li, & Sun, 2017; Yang et al., 2019). Sequentially combining these purification techniques often enhances both purity and recovery. The choice of purification method depends on the targeted iridoid profile and the specific application requirements.

4.3. Analytical methods

Accurate identification and quantification of iridoids require advanced analytical techniques. HPLC-MS is widely accepted as the most reliable approach for iridoid analysis (Du et al., 2018; Niu, Xu, Luo, & Kong, 2016; Wang, Bao, Hao, & Han, 2018). HPLC-MS-MS and HPLC-MSⁿ provide partial structural elucidation through mass fragmentation patterns. Gas chromatography-mass spectrometry (GC–MS) is sometimes employed for volatile iridoid derivatives following derivatization (Kubincova et al., 2016; Niu et al., 2016). Nuclear magnetic resonance (NMR) spectroscopy remains the gold standard for structural determination, providing detailed information on the molecular framework of isolated iridoids (Li et al., 2015). Even though these methods have been applied to the analysis of iridoids, they still exhibit notable limitations. HPLC with mass spectrometry (HPLC-MS) offers high selectivity and sensitivity for the qualitative analysis of target compounds in complex matrices. Tandem mass spectrometry techniques, such as HPLC-MS/MS or HPLC-MSⁿ, provide valuable fragment ion information for partial structural elucidation, although complete structural characterization typically requires purification of targeted compounds and nuclear magnetic resonance (NMR) spectroscopy. Gas chromatography-mass spectrometry (GC–MS) exhibits excellent separation efficiency and is appropriate for volatile or derivatized compounds; however, it is less suitable for highly polar or thermally labile analytes. NMR spectroscopy remains the gold standard for complete molecular structure elucidation, offering detailed structural information, but its application is limited by low sensitivity, high instrument cost, and the requirement for relatively large amounts of purified sample. These methods are increasingly employed for the comprehensive profiling of iridoids in complex plant matrices. Standardization of analytical protocols, including sample preparation, calibration, and validation, is essential to ensure reproducibility and comparability across studies. The establishment of iridoid-specific databases and spectral libraries is essential for optimizing the efficiency and precision of analytical procedures (Ye et al., 2019).

In HPLC-MS analysis, ionization mode and adduct formation critically influence the detection and structural elucidation of iridoids. Both deprotonated ions ([M-H]⁻) and adduct ions such as [M + HCOOH-H]⁻ were observed under negative electrospray ionization (ESI⁻) mode. Notably, loganin and sweroside were detected as formic acid adducts at m/z 435.1506 and 403.12, respectively, while secologanin exhibited a similar adduct at m/z 433.1334. These formic acid adducts likely result from the use of formic acid as a mobile phase additive, which enhances the ionization efficiency of glycosylated iridoids but simultaneously complicates spectral interpretation due to variable adduct formation (Kucharska et al., 2017). Additionally, sodium adducts ([M + Na]⁺) have been previously reported in positive mode (ESI+) for loganin (m/z 413), loganic acid (m/z 399), secologanin (m/z 411), and 7-deoxyloganic acid (m/z 383), suggesting that hydroxyl-rich iridoid glucosides readily coordinate with sodium ions. This is likely facilitated by trace sodium contamination from solvents, glassware, or samples. Such adducts can hinder the rapid identification of iridoids in complex plant matrices by shifting the expected m/z values and reducing fragmentation efficiency. Therefore, careful optimization of ionization parameters and solvent composition, along with the use of authentic standards, is essential for accurate and reproducible detection and quantification of iridoids (Larsen et al., 2017).

5. Dietary sources of iridoids

The content of iridoids in plants is influenced by various factors, including plant sources, seasonal variations, and processing methods. Geographic conditions and seasonal factors, such as growth stage and harvest time, contribute to fluctuations in iridoid concentrations. Additionally, processing conditions, such as drying and extraction methods, can impact the stability and biological activity of iridoids.

5.1. Iridoid-rich plants

Iridoids are widely distributed across various plant families, including Rubiaceae, Scrophulariaceae, Lamiaceae and Plantaginaceae (De Luca et al., 2014; Hussain et al., 2019; Kharb et al., 2022; Thabet et al., 2022). Prominent plant sources include Morinda citrifolia (noni), Cornus officinalis (cornelian cherry), Gentiana lutea (gentian), and Lonicera caerulea (haskap berry or blue honeysuckle) (Deng et al., 2011; Kucharska & Fecka, 2016; Liu et al., 2021; Luca et al., 2019). These plants have been traditionally used in folk medicine, and their iridoid content is attributed to their therapeutic efficacy. Commonly utilized plant parts include fruits, leaves, and roots, with iridoid profiles varying significantly depending on species and cultivars. The data presented in Table 1 highlights the distribution and concentration of major iridoids across various plant species and their respective parts. Notably, L. caerulea berries exhibit the highest iridoid content, with loganic acid ranging from 171 to 326 mg/100 g DW and loganin between 90 and 202 mg/100 g DW. Additionally, the fruit extract contains higher concentrations of iridoids, with loganic acid at 64.3 mg/g DW. In contrast, other plant parts such as the leaves, roots, and seeds of Morinda citrifolia and Caryopteris incana show relatively lower iridoid levels. Furthermore, flowers of Lonicera japonica display notable iridoid content, with swertiamarin (26–43 mg/g DW) and morroniside (2.6–4 mg/g DW). These findings underscore the importance of fruits and flowers as primary sources of iridoids, particularly in species such as L. caerulea, which hold potential for iridoid extraction and utilization (Table 1).

Table 1.

Distribution and concentration of major plant food iridoids.

Dietary sources	Plant Parts	Compounds	Content	References
Lonicera caerulea	Fruit	Loganic acid	171–326 mg/100 g DW	(Kucharska, 2017)
		7-epi-loganic acid 7-O-pentoside	20.3–52.6 mg/100 g DW
		Loganin	90–202 mg/100 g DW
		Sweroside	6.48–15.1 mg/100 g DW
		Secologanin	5.38–15.9 mg/100 g DW
	Fruit extract	Loganin7-O-pentoside	27.0 mg/g DW	(Piekarska, Szczypka, Gorczykowski, Sokół-Łętowska, & Kucharska, 2022)
		Loganic acid 7-O-pentoside	18.0 mg/g DW
		Loganic acid	64.3 mg/g DW
		7-epi-loganic acid 7- Opentoside	28.1 mg/g DW
		Sweroside	110 mg/g DW
	Fruit	Loganic acid	35.2–182.3 mg/100 g FW	(Kucharska et al., 2017)
		7-epi-loganic acid 7-O- pentoside	2.25–45.1 mg/100 g FW
		Loganic acid 7-O-pentoside	9.37–71.2 mg/100 g FW
		7-epi-loganic acid 7-O- pentoside	2.86–19.3 mg/100 g FW
		Sweroside	1.87–71.7 mg/100 g FW
		Loganin	5.85–83.9 mg/100 g FW
		Loganin 7-O- pentoside	1.83–9.11 mg/100 g FW
		Secologanin	3.76–13.3 mg/100 g FW
	Fruit	Loganic acid	4.35–5.73 mg/g DW	(Martinez et al., 2021)
		Loganin	1.11–3.10 mg/g DW
Cornus mas L.	Fruit extract	Loganic acid	183–70,229 mg/100 g DW	(Dzydzan, Brodyak, Sokół-Łętowska, Kucharska, & Sybirna, 2020)
Fructus Corni	Fruit	5-HMF	0.06–0.19 %	(Du et al., 2018)
		Morroniside	0.58–1.61 %
		Sweroside	0.05–0.08 %
		Loganin	0.36–0.64 %
		Cornuside	0.06–0.19 %
Caryopteris incana	Whole plant	Caryocanoside B	ND	(Mao et al., 2016)
		5-Hydroxy-2′′′-O-caffeoylcaryocanoside B	ND
		2′′′-O-(E)-p-Coumaroyl caryocanoside B	ND
		2′′′-O-(Z)-p-coumaroyl caryocanoside B	ND
		2′-O-(E)-p-coumaroyl asystasioside A	ND
Morinda citrifolia Linn.	Fruit	Deacetylasperulosidic acid	3.74 mg/g DW	(Deng et al., 2011)
		Asperulosidic acid	1.25 mg/g DW
	Leaf	Deacetylasperulosidic acid	0.34 mg/g DW
		Asperulosidic acid	0.54 mg/g DW
	Root	Deacetylasperulosidic acid	0.09 mg/g DW
		Asperulosidic acid	0.33 mg/g DW
	Seed	Deacetylasperulosidic acid	1.30 mg/g DW
		Asperulosidic acid	0.15 mg/g DW
	Flower	Deacetylasperulosidic acid	0.88 mg/g DW
		Asperulosidic acid	0.42 mg/g DW
Morinda officinalis how	Root	Monotropein	ND	(Q. Zhang et al., 2020)
		Deacetyl asperulosidic acid	ND
Lonicera japonica Thunb.	Flower	Loganic acid	1.18–3.59 mg/g DW	(Guo et al., 2024)
		Morroniside	2.62–4.00 mg/g DW
		Loganin	5.50–7.51 mg/g DW
		Swertiamarin	26.4–43.2 mg/g DW
		Sweroside	1.95–3.63 mg/g DW
		Secoxyloganin	8.61–12.5 mg/g DW
Lonicerae Japonicae Flos	Flower	7-O-ethyl swertioside	ND	(Yang et al., 2019)
		Secologanin dimethylacetal	ND
		Adinoside F	ND
		(7R)-secologanin n- butyl methyl acetal	ND
		Adinoside G	ND
Linaria canadensis		6’-O-(E)-feruloyl	ND	(Imadzu et al., 2018)
		6’-O-(Z)-feruloyl	ND
		6-O-(E)-feruloyl	ND
		6-O-(Z)-feruloyl	ND
Citharexylum spinosum L.	Flower	Spinomannoside	ND	(Saidi et al., 2020)
		5-deoxypulchelloside I	ND
		pulchelloside I	ND
		Lamiide	ND
		Durantoside I	ND
		Lamiidoside	ND
		Caudatosides B	ND
		Caudatosides E	ND
Dipsacus asper	Root	Loganic acid	ND	(Yu et al., 2020)
		Loganin	ND
		Sweroside	ND
		Sylvestroside I	ND
		Dipsanoside B	ND
		Dipsanoside A	ND
		Dipsacus saponin VI	ND
		3-O-(2-O-acetyl)-α-L-arabinopyranosyl-hederagenin 28 O-β-d-glucopyranosyl-(1–6)-β-D-glucopyranoside	ND
		3-O (3-O-acetyl)-α-L- arabinopyranosyl- hederagenin 28- O-β-D glucopyranosyl-(1–6)-β-D-glucopyranoside	ND
		3-O-(4-O-acetyl)-α-L- arabinopyranosyl-hederagenin 28-O-β-D- glucopyr anosyl-(1- 6)-β-D-glucopyranoside	ND
		Dipsacus saponin A	ND
		Cauloside A	ND
Premna fulva	Leaves	syringaresinol-4′-O-β-D- glucopyranoside	ND	(He et al., 2023)
		eucommin A	ND
		6-O-(3″-O-trans-p-methoxycinnamoyl)-α-L-rhamnopyranosyl catalpol	ND
		6-O-((2″-(3″′-O-trans-p-methoxycinnamoyl)-α-L rhamnopyranosyl)-(3″-O- trans-p-methoxycinnamoyl))-α-L-rhamnopyranosyl catalpol	ND
		6-O-(2″, 4″-di-trans-p- methoxycinnamoyl)-α-L-rhamnopyranosyl catalpol	ND
		6-O-(3″-O-trans-m-methoxycinnamoyl)-α-L-rhamnopyranosyl catalpol	ND
		(−)-pinoresinol-4-O-β-D-glucopyranoside	ND
		Phillyrin	ND
Cymbaria dahurica L.	Whole plant	Loganic acid	0.38–0.58 mg/g DW	(Wang et al., 2018)
		Geniposidic acid	0.43–0.65 mg/g DW
		Catalpol	1.01–1.51 mg/g DW
		Ajugol	0.15–0.36 mg/g DW
		Aucubin	0.72–1.10 mg/g DW
		Cymdahoside	0.13–0.50 mg/g DW
Patriniascabra Bunge	Root	The content of total iridoids	114–507 mg/g DW	(Q. Ma et al., 2022)
Patrinia scabiosifolia Link	whole plant	Patriniscabiosides A	ND	(Sun et al., 2021)
		Patriniscabiosides B	ND
		(4R,5R,7S,8S,9S)-7-hydroxy-8-hydroxymethyl-4-methyl-perhydrocyclopenta[c]pyran-1-one	ND
		6-hydroxy-7-(hydroxymethyl)-4-methylenehexahydrocyclopenta[c]pyran-1(3H)-one	ND
		6-hydroxy-7-methylhexahydrocyclopenta[c]pyran-3-one	ND
		Patrinoside aglucone	ND
		Patrinoside aglucone-11-O-2′- deoxy-β-D-glucopyranoside	ND
		10-acetylpatrinoside	ND
Gentiana rigescens	rhizomes	Loganic acid	ND	(Pan et al., 2015)
		Swertiamarin	ND
		Gentiopicroside	ND
		Sweroside	ND
Eucommia ulmoides	Seeds	Aucubin	ND	(Tang et al., 2021)
		Bartsioside	ND
		Linaride	ND
		Geniposidic acid	ND
		One dimer scy phiphin D	ND
		Two trimers ulmoidoside A	ND
		Ulmoidoside B	ND
		Geniposidic acid	0.68–2.58 mg/g DW	(L. Ma et al., 2022)
		Scyphiphin D	1.65–2.01 mg/g DW
		Ulmoidoside A	24.5–31.9 mg/g DW
		Ulmoidoside C	15.8–22.4 mg/g DW
		Ulmoidoside B	3.85–10.4 mg/g DW
		Ulmoidoside D	0.68–2.58 mg/g DW
Gentiana rigescens	Rhizomes	Loganic acid	ND	(Chen et al., 2017)
		Swertiamarin	ND
		Gentiopicroside	ND
		Trifloroside	ND
Euphrasia rostkoviana	Whole plant	Aucubin	1.10–28.3 mg/g DW	(Mari et al., 2017)
		Geniposidicacid	0.87–6.61 mg/g DW
		Mussaenosidicacid	4.88–13.4 mg/g DW
Pseudolysimachion Rotundum var. subintegrum	Seeds	Verproside	85.4 mg/g DW	(Song et al., 2023)
		Catalposide	9.36 mg/g DW
		Picroside II	11.7 mg/g DW
		Verminoside	9.15 mg/g DW
		Isovanillyl catalpol	24.2 mg/g DW
		6-O-Veratroyl catalpol	12.9 mg/g DW
Gardenia jasminoides	Leaves Flower Fruit	Shanzhiside methyl ester	ND	(Ye et al., 2019)
		Shanzhiside	ND
		Gardenoside	ND
		Geniposide	ND
		Genipin	ND
		Geniposidic acid	ND
		Genipin-1-β-gentiobioside glycosides	ND

DW, dry weight; FW, fresh weight; ND, no data.

5.2. Geographic and seasonal variations

The iridoid content in plants is influenced by geographic location, climatic conditions, and seasonal variations. For instance, plants cultivated at higher altitudes or in soils with specific compositions often exhibit elevated iridoid concentrations (Thabet et al., 2022). Seasonal factors, particularly harvest time, play a critical role, with peak iridoid levels typically observed at specific growth stages. Understanding these variations is essential for optimizing the iridoid content in candidate plant sources. For instance, in Lonicera × bella (Bella Honeysuckle), the highest concentrations of iridoid glycosides, particularly secologanin, were found in the leaves during the flowering and fruiting stages. These reproductive phases led to a significant increase in iridoid glycosides levels, with concentrations approximately twice as high as those observed during earlier stages, such as leaf-out, and later stages, such as fruit dispersal. This emphasizes the role of phenological stages in regulating the content of iridoid glycosides in plants (Blanchard & Bowers, 2020).

5.3. Processing effects

Processing methods, including drying, extraction, and storage, significantly influence the stability and bioavailability of iridoids (Wang, Gong, et al., 2020). For example, high-temperature drying can degrade heat-sensitive iridoids, whereas freeze-drying preserves their structural integrity (Ma, Meng, et al., 2022). Storage factors, such as temperature, moisture, and light exposure, also affect iridoid stability. Recent advancements, including encapsulation and freeze-drying techniques, are increasingly employed to maintain iridoid content and enhance product shelf life. For instance, in Eucommia ulmoides Oliv., the iridoids geniposidic acid, scyphiphin D, ulmoidoside A, ulmoidoside B, ulmoidoside C, and ulmoidoside D were identified from seed meal, a by-product of seed oil extraction. Stability assessments revealed that geniposidic acid remained stable under all tested conditions. In contrast, scyphiphin D, ulmoidoside A, and ulmoidoside C exhibited hydrolytic degradation only under strongly alkaline conditions, whereas ulmoidoside B and ulmoidoside D were more sensitive, showing significant degradation under elevated temperatures as well as acidic and alkaline environments (Ma, Meng, et al., 2022; Neri et al., 2018). In L. caerulea L., the combination of XAD resin with spray-drying or freeze-drying techniques enhanced the concentration of iridoids, particularly loganic acid, 7-epi-loganin, and pentosyl-loganin (Michalska-Ciechanowska et al., 2024). In Nepeta cataria L., the iridoids E, Z-nepetalactone and dihydronepetalactone were detected, with light exposure accelerating the degradation of E, Z-nepetalactone, while dihydronepetalactone remained stable (Lockhart, Simon, & Wu, 2024). In Genipa americana L., the major iridoid components identified included genipin, genipin 1-β-gentiobioside, and geniposide. The study found that these compounds were most stable under low pH conditions (3.0–4.0) and at temperatures ranging from 12 to 20 °C (Neri et al., 2018).

6. The role of iridoids in maintaining human health

Iridoids have shown considerable potential as bioactive compounds, offering a broad spectrum of health benefits. This section discusses their antioxidant, anti-inflammatory, and metabolic effects, as well as their promising role in functional foods aimed at promoting human health and preventing chronic diseases.

6.1. Antioxidant activity

Iridoids exhibit significant antioxidant properties that mitigate oxidative stress as well as pre-clinical evidence supporting their health benefits against chronic diseases. A limited number of clinical trials have demonstrated that iridoid-rich extracts can improve biomarkers of oxidative stress, inflammation, and metabolic health in patients with chronic conditions. Iridoid compounds gardenoside, geniposide, and unedoside extracted from Arbutus unedo L. exhibited significant antioxidant activity (Tenuta et al., 2020). Loganic acid, the most abundant iridoid of L. caerulea, scavenge free radicals and amplify the function of endogenous antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT) (Dzydzan et al., 2020). The antioxidant properties of iridoids, such as catalpol, swertiamarin, geniposide, loganin, oleuropein, have been established in various in vitro and in vivo experimental models, revealing their capacity to diminish oxidative damage associated with chronic diseases such as cardiovascular diseases and type 2 diabetes (Danielewski et al., 2020; Zhou, Tian, Li, & Yu, 2024).

6.2. Anti-inflammatory effects

Iridoids display significant anti-inflammatory properties by controlling key inflammatory signaling pathways and lowering the production of pro-inflammatory mediators. Research on the iridoids, monotropein and deacetyl asperulosidic acid, extracted from Morinda officinalis, has demonstrated their ability to inhibit the activation of nuclear factor-kappa B (NF-κB). Furthermore, these compounds effectively reduce the levels of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (Zhang et al., 2020). Iridoids such as shanzhiside methyl ester and phlorigidoside C have been identified as viable candidates for managing chronic inflammatory conditions, including arthritis, inflammatory bowel disease, and neuroinflammation (Zhao et al., 2021).

6.3. Metabolic health

The beneficial effects of iridoids on metabolic health are linked primarily to their ability to regulate lipid metabolism. For instance, total iridoid glycosides of Picrorhiza scrophulariiflora have been shown to improve liver metabolism in rats with non-alcoholic steatohepatitis (NASH). The extract reduces liver lipid accumulation, alleviates inflammation and oxidative stress, and enhances metabolic function, thereby mitigating insulin resistance and fatty liver development (Xu et al., 2020). For example, patrinoside A has been reported to enhance insulin sensitivity and stimulate glucose uptake in 3 T3-L1 adipocytes in vitro (Liu et al., 2019). Additionally, iridoids exhibit protective effects against lipid and cholesterol-associated metabolic dysfunctions in both the liver and cardiovascular systems. Gentiopicroside supports metabolic health by regulating fatty acid synthesis, reducing triglyceride accumulation, and reducing the risk of fatty liver disease. Geniposide improves liver metabolism by reducing fibrosis and regulating fatty acid metabolism through transforming growth factor (TGF)-β1 inhibition. Catalpol supports metabolic health by reducing fibrosis, lowering liver enzymes, and modulating peroxisome proliferator-activated receptor (PPAR)-α, while decreasing inflammation. These iridoids protect metabolic health through their modulation of lipid metabolism and inflammation (Danielewski et al., 2020; Danielewski, Matuszewska, Szeląg, & Sozański, 2021). Iridoids, including gentiopicroside, geniposide, catalpol, swertiamarin, and amarogentin, confer metabolic protection against type 2 diabetes and hyperlipidemia. These compounds improve insulin resistance, regulate blood glucose levels, and enhance insulin secretion. Additionally, they modulate lipid metabolism by reducing triglyceride accumulation, lowering serum cholesterol, and decreasing pro-inflammatory signal molecules (Danielewski et al., 2020). However, further well-designed, human clinical studies are needed to confirm these findings and elucidate the underlying mechanisms.

6.4. Neuroprotective effects

Iridoids contribute to neuroprotection by attenuating oxidative stress, inflammation, and apoptotic pathways in neuronal cells (Dinda, Dinda, Kulsi, Chakraborty, & Dinda, 2019). Iridoid-rich extracts from Gardenia jasminoides and Cornus officinalis were reported to enhance mitochondrial function and attenuate oxidative stress-induced neuronal damage in experimental animal models (Gao, Liu, An, & Ni, 2021; Jin et al., 2023). Emerging evidence also suggests that dietary sources of iridoids, may delay the onset of neurodegenerative disorders (Dinda et al., 2019). Despite these promising pre-clinical findings, human clinical trials are needed to confirm their therapeutic potential and to elucidate dose-response relationships in humans (Przybylska et al., 2023).

6.5. Antitumor activity

Iridoids have shown promising anti-cancer and antitumor properties by inducing apoptosis, inhibiting cell proliferation, and suppressing angiogenesis in various cancer models. For instance, genipin has been shown to inhibit the proliferation of breast cancer (MCF-7) and glioblastoma cells. 1-epi-Bosnarol demonstrates significant inhibitory activity against cervical (HeLa), ovarian (A2780), and breast (T47D) cancer cell lines. Jatamanvaltrate P suppresses the migration of triple-negative breast cancer MDA-MB-231 cells, induces apoptosis, and achieves a tumor growth inhibition rate of 49.7 % in vivo (Ndongwe et al., 2023). Iridoid glycoside oleuropein suppresses MMP activity and reduces angiogenesis by modulating vascular endothelial growth factors (VEGF) and cluster of differentiation 31 (CD31), demonstrating their potential to slow cancer progression and metastasis (Kim & Choi, 2021). Despite these encouraging findings, thorough mechanistic studies and systematically planned clinical trials are vital to confirm their mode of action and effectiveness in cancer prevention and management.

6.6. Antiviral activity

Iridoids have demonstrated notable antiviral activities against a range of pathogens, such as hepatitis B virus (HBV) (Frezza et al., 2024). 8-O-(E-p-Methoxycinnamoyl) harpagide (MCH) exhibits antiviral activity against influenza A virus (IAV) by inhibiting viral protein expression, interacting with the M2 protein, and reducing intracellular Ca²⁺/ROS levels, suggesting its potential for IAV treatment development (Kwon, Yang, Kim, Li, & Choi, 2021). The anti-inflammatory and antioxidant properties of iridoids further contribute to mitigating virus-induced tissue damage and promoting recovery (Kim & Choi, 2021). These findings highlight iridoids as promising candidates for developing natural antiviral agents, though further mechanistic studies and clinical validations are necessary to confirm their therapeutic potential.

6.7. Hepatoprotective effects

Iridoids exhibit remarkable hepatoprotective effects, making them potential candidates for preventing and treating liver-related disorders. Iridoids such as geniposide, aucubin, and catalpol have been shown to protect hepatocytes from damage caused by oxidative stress, inflammation, and toxic insults (Bridi, von Poser, & de Carvalho Meirelles, 2023; Zeng et al., 2024). Geniposide mitigates liver injury by suppressing inflammatory pathways, including NF-κB activation, and enhancing antioxidant defenses through Nrf2-mediated signaling (Zeng et al., 2024; Zhang et al., 2020). Similarly, aucubin has demonstrated protective effects in alcoholic liver disease models by reducing lipid peroxidation and promoting mitochondrial function (Zhang, Feng, et al., 2020). These observations suggest that iridoids can effectively mitigate liver damage and promote hepatic function, although clinical trials are required to verify their safety and efficacy in humans.

Overall, the diverse bioactivities of iridoids underscore their potential as natural compounds for promoting human health and preventing chronic diseases. Continued research, including clinical validation and mechanistic studies, is essential to fully harness the therapeutic potential of iridoids. The health-promoting effects of iridoids are demonstrated through diverse experimental studies, presented in Table 2. Iridoids exhibit antioxidant, anti-inflammatory, antidiabetic, and anticancer activities in vitro and in vivo. Notable findings include enhanced antioxidant capacity during simulated digestion, inhibition of nitric oxide production, and regulation of lipid metabolism and oxidative stress in nonalcoholic steatohepatitis (NASH) models. Additionally, iridoids improve insulin resistance through the PI3K/Akt pathway, and exhibit antibacterial effects (Fig. 3). These results emphasize the therapeutic potential of iridoids in addressing oxidative stress, inflammation, metabolic disorders, and related health conditions.

Table 2.

Experimental in vitro and in vivo evidence of potential health benefits of iridoids.

Biological activity	Model	Main findings	References
In vitro experimental models
Antioxidant	Simulated gastric digestion (pH 2–7)	Stable color at 12–20 °C and pH 3.0–4.0; Antioxidant capacity increased by 17–18 % (general digestion) and 39 % (ORAC assay).	(Neri-Numa et al., 2018)
Anti-hepatoma	Antioxidant and anti-hepatocarcinoma assays	Strong antioxidant activity. Significant anti-hepatocarcinoma activity observed.	(Lu et al., 2016)
Antidiabetic	Yeast α-glucosidase inhibition assay	Compounds exhibited potent α-glucosidase inhibitory activity, indicating potential. Antidiabetic effects.	(Mao et al., 2016)
Anti-inflammatory	RAW 264.7 cells; LPS-induced nitric oxide production assay	Iridoids showed inhibitory effects on nitric oxide production.	(Lee et al., 2018)
Anti-inflammatory	RAW264.7 macrophage cells treated with LPS	Refined iridoid extract significantly inhibited NO production and reduced inflammatory markers (COX-2, iNOS) with IC50 of 10.49 μg/mL. These effects suggest potential for managing inflammatory-related conditions in humans.	(Liu et al., 2021)
Antioxidant, hypoglycemic, and anti-inflammatory	ABTS, DPPH, α-glucosidase inhibition, NO inhibition assays	Extracts of Arbutus unedo L. leaves and fruits exhibited strong antioxidant (IC50: 0.42 μg/mL), hypoglycemic (IC50: 19.56 μg/mL), and anti-inflammatory activities, linked to flavonoids and iridoids identified by LC-ESI-QTOF-MS.	(Tenuta et al., 2020)
Antioxidant	FRAP, DPPH, and Folin-Ciocalteu assays	Sustainable extraction of polyphenols and iridoids from medicinal plant by-products (STF231) using choline chloride:lactic acid (1:5) yielded high TPCs and potent antioxidant activity, supporting health applications and environmental sustainability.	(Marchetti et al., 2024)
Antioxidant and antibacterial	HRMS, PCA, and bioassays	All parts of Barleria prionitis contain bioactive iridoid glycosides and phenolic compounds, with roots showing the strongest antioxidant and antibacterial activities, correlated to specific compounds identified.	(Singh et al., 2023)
Insulin resistance improvement	3 T3-L1 adipocytes, Western blot	Two iridoid glycosides from Patrinia scabiosaefolia improved insulin sensitivity via PI3K/Akt activation.	(Liu et al., 2019)
Anti-inflammatory	LPS-induced RAW264.7 cells	Potent anti-inflammatory activity by inhibiting NO production in RAW264.7 cells.	(Guo et al., 2024)
Antibacterial, Antiproliferative	Enterococcus faecalis, Bacillus subtilis, NB4 (acute leukemia), K562 (chronic leukemia)	Iridoids showed antibacterial activity and inhibited NB4 and K562 leukemia cell proliferation by inducing apoptosis and G2/M arrest.	(Saengsai et al., 2015)
Antioxidant	Antioxidant assay	Extracts showed antioxidant activity, as measured by FRAP and DPPH assays.	(Náthia-Neves et al., 2017)
Anti-tyrosinase, Anticholinesterase, Cytotoxic	Tyrosinase inhibition, Cholinesterase inhibition, Human cervical cancer cell line (HeLa).	Caudatoside E showed the highest anti-tyrosinase (69.3 ± 2.8 % inhibition) and anticholinesterase activity (IC50 = 22.38 ± 1.82 μM).	(Saidi et al., 2020)
Anti-inflammatory, Anti-proliferative	Anti-inflammatory: NO production inhibition in stimulated cells. Anti-proliferative: MCF-7 breast cancer cell line.	Iridoids significantly inhibited NO production, and anti-proliferative activity against MCF-7 cells.	(Liu et al., 2024)
Anti-inflammatory	LPS-stimulated RAW 264.7 macrophage cells	Three were new iridoid glycosides showed potential anti-inflammatory effects.	(He et al., 2023)
Anti-inflammatory	LPS-stimulated microglial cells	Iridoid glycosides significantly inhibited NO production without cytotoxicity.	(Tang et al., 2021)
In vivo experimental models
Anti-inflammatory, Anti-arthritic	In vivo: Mice. In vitro: RAW 264.7 macrophages.	Iridoids reduced inflammation and inhibited MAPK, NF-κB pathways.	(Q. Zhang et al., 2020)
Immunotropic	Mice infected with Trichinella spiralis	Iridoid-anthocyanin extract modulated the immune response in mice during T. spiralis infection by stimulating splenocyte proliferation and altering the percentages of immune cells (B and T cells) in peripheral blood.	(Piekarska et al., 2022)
Anti-fatty liver, lipid metabolism regulation	High-fat, high-sugar diet-induced NASH rats.	Iridoid improved NASH by regulating lipid metabolism, reducing insulin resistance, and inhibiting oxidative stress and inflammation.	(Xu et al., 2020)
Antidiabetic and antioxidant effects	Streptozotocin-induced diabetic rats	Loganic acid enhanced antioxidant activity and reduced ROS.	(Dzydzan et al., 2020)
Anti-inflammatory,	Animal models	Optimized extraction enhanced iridoids, showing analgesic effects.	(Q. Ma et al., 2022)

Abbreviations: ORAC: Oxygen Radical Absorbance Capacity; LPS: Lipopolysaccharide; NO: Nitric Oxide; COX-2: Cyclooxygenase-2; iNOS: Inducible Nitric Oxide Synthase; IC50: Half Maximal Inhibitory Concentration; ABTS: 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); DPPH: 2,2-Diphenyl-1-picrylhydrazyl; LC-ESI-QTOF-MS: Liquid Chromatography-Electrospray Ionization-Quadrupole Time-of-Flight Mass Spectrometry; FRAP: Ferric Reducing Antioxidant Power; TPC: Total Phenolic Content; HRMS: High-Resolution Mass Spectrometry; PCA: Principal Component Analysis; PI3K/Akt: Phosphoinositide 3-Kinase/Protein Kinase B; MAPK: Mitogen-Activated Protein Kinase; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B cells; NASH: Non-Alcoholic Steatohepatitis; ROS: Reactive Oxygen Species.

Fig. 3.

Biological effects of iridoids on human health.

① Iridoids serve as antioxidants and reduce oxidative damage by reducing reactive oxygen species (ROS) and activation of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT); ② Anti-inflammatory effects of iridoids prevent inflammatory diseases by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), pro-inflammatory cytokines (e.g., IL-6, TNF-α), and reducing overall chronic inflammation; ③ Iridoids improve lipid and cholesterol metabolism, promoting glucose uptake, thus contributing to metabolic health; ④ Iridoids reduce neuronal damage by enhancing mitochondrial function and decreasing oxidative stress, which helps protect nerve cells and support brain health; ⑤ Additionally, iridoids reduce tumor size and metastasis by inhibiting vascular endothelial growth factor (VEGF), a key factor in controlling tumor growth and spread; ⑥ Iridoids exhibit antiviral effects by inhibiting viral proteins, lowering Ca²⁺/ROS levels, and providing anti-inflammatory benefits, suggesting their potential for antiviral therapy; ⑦ Iridoids exhibit antiviral effects by inhibiting viral proteins, lowering Ca²⁺/ROS levels, and providing anti-inflammatory benefits, suggesting their potential for antiviral therapy. Abbreviations: VEGF, Vascular endothelial growth factor; IV, Intravenous; MCH, 8-O-(E-p-methoxycinnamoyl) harpagide; IAV, Influenza A virus; Nrf2, Nuclear factor erythroid 2-related factor 2; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, Phosphoinositide 3-kinase; IL-6, Interleukin-6; TNF-α, Tumor necrosis factor alpha; GLUT-4, Glucose transporter type 4; SOD, Superoxide dismutase; CAT, Catalase; ROS, Reactive oxygen species.

7. Industrial applications of iridoids

Iridoids exhibit potential for versatile applications in functional foods, nutraceuticals, pharmaceuticals, and cosmetics. Iridoid-rich extracts or dehydrated plant materials can be used as functional food ingredients to supplement beverages and healthy snacks, develop nutraceuticals and formulate cosmeceuticals (Fig. 4). Isolated iridoids and their derivatives can be used as drugs or drug leads, and their effectiveness can be improved using advanced delivery systems such as nano-encapsules and nano-emulsions (Kharb et al., 2022).

Fig. 4.

Major potential industrial applications of iridoids. A: Functional foods and nutraceuticals, iridoids enhance nutrition and health benefits of beverages, dietary supplements, and snacks; B: Pharmaceuticals, iridoids can be used in drug delivery with the applications of nanoencapsulation and liposomes; C: Cosmetics, iridoids can be incorporated in creams, serums, and lotions to protect against oxidative damage and aging; D: Industrialization challenges, extraction, regulation, and sustainable production limit iridoid applications in health, wellness, and beauty; E: Chemical & biotechnology, future research need to aim at iridoid synthesis using organic chemistry, synthetic biology and other biotechnological approaches and through metabolic engineering.

7.1. Functional foods and nutraceuticals

The potential for incorporating iridoid-rich ingredients into functional foods and nutraceuticals owing to their bioactive properties has been suggested. Iridoids are widely present in various natural functional foods and beverages, with their concentrations varying significantly across products. In noni fruit (Morinda citrifolia) juice, the total iridoid content, primarily deacetyloasperulosidic acid and asperulosidic acid, is about 166 mg/100 mL. Virgin olive oil contains 93 mg/100 mL of oleuropein, 8.5 mg/100 mL of oleuropein aglycone, and 28 mg/100 mL of ligstroside. Bilberry (Vaccinium myrtillus) juice provides 206 mg/100 mL of total iridoids, whereas bilberry wine contains a lower concentration of 64.4 mg/L. Dried Fructus corni fruit displays the highest iridoid content among the listed products, ranging from 2610 to 3000 mg/100 g. Processed products such as cornelian cherry (Cornus mas) jam contain 48–128 mg/100 g of iridoids, including loganic acid and cornuside. Among supplemented food, honeysuckle berry-incorporated yogurt contains 60–189 mg/L of total iridoids (Heffels, Müller, Schieber, & Weber, 2017; Medina, De Castro, Romero, & Brenes, 2006; Potterat & Hamburger, 2007; Przybylska et al., 2023). Antioxidant, anti-inflammatory, and metabolic health advantages of iridoids render them excellent candidates for boosting the nutritional and therapeutic value of functional foods. For instance, iridoid-enriched beverages, dietary supplements, and fortified snacks can be developed to promote human health and prevent chronic diseases (Kucharska, 2017; Saidi et al., 2020).

7.2. Pharmaceuticals

The pharmacological potential of iridoids in the development of pharmaceutical products has been discussed. Notably, Oleuropein, a major secoiridoid in virgin olive oil, has shown protective effects against diabetes mellitus. Morroniside, loganin, and loganic acid, widely found in Cornus species, also possess significant anti-diabetic activity. Loganic acid, in particular, has been associated with glycation inhibition, which is crucial in preventing diabetes-related complications. Additionally, cornuside and cornin contribute to glycemic control and metabolic protection, supporting their potential as natural agents in diabetes management. (Przybylska et al., 2023). Scientific evidence supports the potential of iridoids as promising natural compounds for drug development, particularly in the treatment of diseases such as cardiovascular and neurodegenerative disorders. Notable examples include oleuropein and cornin (Danielewski et al., 2020; Przybylska et al., 2023; Wang, Gong, et al., 2020; Wang, Zheng, et al., 2024). Their ability to modulate critical biological pathways makes them valuable for the formulation of natural-based therapeutics. Advancements in drug delivery systems further improve the bioavailability and efficacy of iridoid-based pharmaceuticals (Arraché Gonçalves et al., 2022).

7.3. Cosmetics

In the cosmetics sector, iridoids have potential use as active ingredients due to their antioxidant and anti-inflammatory properties, which can protect the skin from UV-induced oxidative stress and mitigate the visible effects of aging. For instance, the iridoids extracted from Cornus mas L. exhibited notable tyrosinase inhibitory activity, suggesting their potential role in skin-whitening formulations (Nizioł-Łukaszewska, Wasilewski, Bujak, & Osika, 2017). Iridoid-containing formulations, such as creams, serums, and lotions, are marketed for their ability to improve skin health, elasticity, and hydration. Genipin, a product of the enzymatic hydrolysis of iridoid glycosides such as geniposide, forms stable blue and red pigments upon reacting with amino acids. In addition to its coloring properties, genipin also demonstrates significant antioxidant activity. These characteristics position genipin as a promising natural colorant for cosmetic applications (Jin et al., 2023). Moreover, their natural origin and biocompatibility align with the increasing consumer demand for clean and sustainable beauty products (Jin et al., 2023; Neri et al., 2018; Tang et al., 2021).

7.4. Challenges in industrialization

Despite their potential, the industrial application of iridoids faces several challenges. One significant obstacle is the cost-effective extraction and purification of iridoids from natural sources, as large-scale production often requires substantial resources and advanced technologies. In general, the content of iridoids in plants ranges from 9 to 573 mg/100 g DW (Table 1). Moreover, the stability of iridoids during manufacturing and storage creates obstacles to product development and shelf stability (Ma, Meng, et al., 2022).

Regulatory approval and standardization are also critical barriers, as variability in iridoid content and quality across different sources can affect product efficacy and safety (Kuzina, Malashenko, & Eller, 2022). Overcoming these challenges through technological innovations, such as biotechnological production, metabolic engineering, and sustainable extraction methods, are essential for the successful industrialization of iridoid-based products. Addressing these barriers will enable iridoids to have the potential to transform various industries, offering innovative solutions for health, wellness, and beauty.

8. Conclusions and future perspectives

Iridoids are a category of bioactive phytochemicals with various health-enhancing properties and substantial potential for industrial applications. Their antioxidant, anti-inflammatory, and other desirable biological activities suggest their potential to be used in the development of functional foods, nutraceuticals, and cosmetics. In the food sector, iridoids can be utilized in functional foods and beverages, enhancing both disease-preventive and therapeutic benefits. Their ability to improve oxidative stability and extend shelf-life positions iridoids as an attractive ingredient and additive for food preservation and health-focused food formulations. Advances in extraction, purification, and analytical techniques have significantly enhanced the potential utilization of iridoids; however, challenges persist in large-scale production, stability, and regulatory approval.

Future research should focus on addressing these challenges by developing sustainable and cost-effective production methods, such as biotechnological synthesis, metabolic engineering and precision agriculture of selected cultivars. Furthermore, additional clinical investigations are pivotal to affirming the health benefits of iridoids and illuminating their mechanisms of action. Collaborative efforts among academia, industry, and regulatory agencies will be pivotal in translating iridoid research into innovative products. By fully harnessing the potential of iridoids, it is possible to contribute to improved health outcomes through the development of sustainable, supplemented functional foods, nutraceuticals, and cosmetic products. The continued exploration of iridoids holds the promise of unlocking new opportunities to enhance human health and well-being.

CRediT authorship contribution statement

Liangchuan Guo: Writing – original draft, Visualization, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Jinli Qiao: Writing – review & editing, Visualization, Software, Methodology, Formal analysis. Junwei Huo: Writing – review & editing, Supervision, Resources, Funding acquisition, Conceptualization. H.P. Vasantha Rupasinghe: Writing – review & editing, Validation, Supervision, Resources, Project administration, Investigation, Funding acquisition, Conceptualization.

Funding

The authors acknowledge the financial support from the National Key Research and Development Program of China (2022YFD1600500), the Natural Sciences and Engineering Research Council (NSERC, Grant number RGPIN2023-03324) of Canada, and the China Scholarship Council (202406610002).

Declaration of competing interest

The authors have no conflict of interest to declare.

Data availability

No data was used for the research described in the article.