Hypolipidemic effect of cynaroside involves four aspects: regulation of the cholesterol metabolism, suppressing lipid synthesis and enhancing lipolysis, reducing blood lipid by exerting estrogen-like effects, and regulating the gut microbiota and its metabolites (Figure 3).

Inflammation and lipid metabolism disorders form a vicious circle through immune-metabolic interactions, which jointly drive the pathological process of many chronic diseases. The interaction mechanism of inflammation and lipid metabolism is shown in Figure 4. In inflammatory conditions, pro-inflammatory factors, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) inhibit lipoprotein lipase activity and LDL receptor expression in hepatocytes, resulting in impaired TG breakdown, reduced LDL-C clearance and increased VLDL synthesis (Saltiel and Olefsky, 2017). Lipid disorders can also further activate the immune system. Free fatty acids (FFA) trigger macrophage inflammatory response through toll-like receptor 4 (TLR4)/nod-like receptor protein 3 (NLRP3) inflammasome pathway. And cholesterol crystals and oxidized LDL (ox-LDL) promote T cell activation and pro-inflammatory factors release through scavenger receptor mediated foam cell formation and antigen presentation, forming a chronic low-grade inflammatory microenvironment (Ouchi et al., 2011; Kawai et al., 2021).

Numerous studies have shown the strong anti-inflammatory properties of cynaroside isolated from various plants, consolidating its role as a promising therapeutic agent. Table 1 presents the key studies exploring the underlying mechanisms of these activities of cynaroside. The modulation of involved signaling pathways is summarized in Figure 5. Cynaroside not only blocks the interaction between ligands (pathogen-associated molecular patterns, PAMPs) and their receptor (pattern recognition receptors, PRRs), but also inhibits the activation of downstream signaling nuclear factor kappa-B (NF-κB), NLRP3 and janus kinase/signal transducer and activator of transcription (JAK/STAT) inflammatory pathways (Surh et al., 2001; Fujioka et al., 2004; Bouyahya et al., 2023).

NF-κB consists of p65 and p50, serving as transcription factors that regulate the expression of genes involved in inflammation, cell differentiation and proliferation (Surh et al., 2001). Activator protein-1 (AP-1) is a ubiquitous protein that exists in the cytoplasm as homodimer or heterodimer with the jun and fos families (Fujioka et al., 2004). The activation of NF-κB and AP-1 is highly correlated with the induction of inflammatory enzymes and is regulated by the phosphorylation of p65 and c-jun. Therefore, NF-κB and AP-1 are considered key therapeutic targets for suppressing inflammatory responses (Kim et al., 2013). Park and Song (2013) found that cynaroside effectively inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and inhibited the expression of the corresponding enzymes, like inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), which was associated with downregulation of the NF-κB/AP-1/PI3K-Akt pathway. In vitro, inhibition of lipopolysaccharide (LPS)-stimulated RAW 264.7 cells showed that cynaroside inhibited the production of NO and PGE2 by inhibiting p65 and c-jun translocation, suppressing the activation of NF-κB and AP-1, and reducing the protein expression of iNOS and COX-2 (Park and Song, 2013). Han et al. (2023) treated mice infected with Toxoplasma gondii (T. gondii) with different doses of cynaroside (0, 50, 100, 200 mg/kg for 7 days) and further detected the expression of key proteins in inflammatory and oxidative stress related pathways in the liver. The results showed that cynaroside significantly reduced inflammatory factors TNF-α, IL-6, and IL-1β, as well as the oxidative product malondialdehyde (MDA), while significantly increasing antioxidant enzymes superoxide dismutase (SOD) and glutathione (GSH). Moreover, key proteins in the TLR4/NF-κB pathway, including TLR4, myeloid differentiation primary response 88 (Myd88), TNF receptor associated factor 6 (TRAF6) and p-NF-κB p65, were all significantly downregulated in the mouse liver. This confirms that cynaroside can inhibit T. gondii induced liver injury by blocking inflammatory response and enhancing antioxidant capacity. TLR4 is a member of the toll-like receptor family, which can promote the activation of NF-κB signaling pathway (Peng et al., 2016).

The NLRP3 inflammasome is a multiprotein complex in the innate immune system. Its dysregulation can drive chronic inflammation in diseases, making it a key therapeutic target for modulating inflammatory pathways (Xu et al., 2024). Purinergic 2X7 Receptor (P2X7R) is an inflammatory receptor involved in the activation of inflammatory vesicles NLRP3, which can further upregulate the release of inflammatory factors, such as IL-18 and IL-1β (Han et al., 2018). Han et al. (2023) also verified that the expressions of key proteins in the P2X7R/NLRP3 pathway, including P2X7R, NLRP3, caspase 1, IL-1β and IL-18, were significantly reduced in the liver of rats infected with T. gondii. The results of Lang et al. (2024) consistently demonstrated that cynaroside could inhibit NLRP3 inflammasome activation in rats induced by methotrexate. The study used 7 mg/kg of methotrexate to treat Sprague-Dawley rats for 3 days, followed by treatment with different doses (10, 20, 40 mg/kg) of cynaroside for 7 days, to evaluate the protective potential of cynaroside against intestinal inflammation. The results showed that administration of 20 or 40 mg/kg of cynaroside reduced inflammatory cell infiltration in the intestines induced by methotrexate, increased the number of goblet cells, decreased serum levels of TNF-α, IL-1β, and IL-18, as well as the rate of CD68-positive cells. In addition, cynaroside increases ICEBERG (caspase-1 inhibitor) levels by blocking IL-1β secretion and suppressing the activation of the NLRP3 inflammasome.

During the process of vascular inflammation, the activation of the JAK/STAT3 pathway is a key mechanism for regulating endothelial cell inflammation, migration, and proliferation of vascular smooth muscle cells (VSMCs) (Zegeye et al., 2018). IL-6 stimulates JAK and promotes gp130 phosphorylation of JAK, which induces the phosphorylation and dimerization of STAT3. STAT3 then translocates to the nucleus to activate the expression of pro-inflammatory genes (Moshapa et al., 2019). It is important to note that it has been demonstrated in keratinocytes that cynaroside can downregulate inflammation-related target genes by inhibiting the damage of STAT3 nuclear translocation, which counteracts JAK/STAT3 pathway activated by IL-22 and IL-6 (Palombo et al., 2016). De Stefano et al. (2021) elucidated that cynaroside exerted antiproliferative effects by inhibiting the STAT3 pathway in human umbilical vein endothelial cells (HUVEC), and down-regulating the transcription of IL-1β, IL-6 and TNF-α, thereby exerting antioxidant and anti-inflammatory effects. Using cultured HUVEC, cynaroside was treated at a concentration of 20 µM for 48 h, and RNA was extracted and analyzed for many genes in inflammatory pathways. Cynaroside interventions significantly inhibited a variety of cytokines and related receptors involved in the inflammatory pathway, the chemokines and their receptors that were downregulated included C-C motif ligand (CCL)1-3, CCL19, CCL21, C-C motif receptor (CCR)7, CCR8, C-X-C motif chemokine ligand (CXCL)2, CXCL8, CXCL9 and CXCL12. CCL1 is a T-cell chemokine that mediates monocyte chemotaxis and immune regulation. CCR8 is a key transmembrane receptor for inflammatory cell migration that interacts with CCL1 (Haque et al., 2001). Parallel downregulation patterns are observed in CCL11 (eosinophil chemoattractant via CCR3) and CCL3 (macrophage-activating cytokine), both key mediators of inflammatory cascades (Kindstedt et al., 2017; Li et al., 2024). Cynaroside similarly suppresses CXCL12, a multifunctional chemokine involved in lymphocyte/monocyte recruitment, tumor surveillance, and metastasis regulation (Conley-LaComb et al., 2016). Leukotriene B4 receptor (LTB4R) is a lipid mediator receptor in metabolism pathways of arachidonic acid, and IL-1β is a central inflammatory cytokine (Libby, 2017). Their reduction further confirms the broad anti-inflammatory effects of cynaroside. Palombo et al. (2016) found that in the imiquimod murine model of psoriasis, cynaroside treatment blocked the nuclear translocation of phosphorylated STAT3 induced by the stimulation of proinflammatory cytokines IL-22 and IL-6, thus exerting anti-proliferative and anti-inflammatory effects.

Ji-Eun et al. (2024) further demonstrated that cynaroside reduced the expression of inflammatory molecules such as ICAM-1, VCAM-1, TNF-α, IL-1β and COX-2, and reduced reactive oxygen species (ROS) formation by inhibiting the activation of p-JNK in the MAPK pathway, thus exerting a protective effect against inflammation and oxidative stress in methylglyoxal-induced human dental pulp cells. Canh Pham et al. (2024) also extracted cynaroside from V. amygdalina leaf and found that cynaroside had a very high affinity (>10 kcal/mol) for iNOS and COX-2. Jalil et al. (2003) confirmed the anti-inflammatory activity of cynaroside in vitro by studying the inhibitory effect of four total extracts (dichloromethane, methanol, 50% methanol, water extract) and their main active ingredients (cynaroside) on human neutrophils induced by the aerial parts of Carthamus lanatus L.

Oxidative damage is undeniably responsible for lipid-related metabolic disease progression. Intracellular oxidative stress is caused by the imbalance between the level of ROS and antioxidant defense. If excessive ROS is produced by oxygen enzymes along the respiratory chain, it will cause DNA damage, protein crosslinking, lipid peroxidation of polyunsaturated fatty acids and further lead to cell aging, cell membrane damage, etc. (Barrera, 2012). In many cases, inflammation and oxidative stress are mutually promoted and activated. Amounts of studies also have demonstrated the strong antioxidant properties of cynaroside (Table 1; Figure 5).

Dong et al. (2023) first found that cynaroside as a flavonoid compound had in vitro antioxidant capacity and delayed the oxidation of LDL in a dose-dependent manner. The antioxidant activity is partly related to its flavonoids, which are chelators of hydrogen donors and metal ions. It can chelate Fe²⁺ through its C ring, thus avoiding the formation of the most harmful ROS (OH-). And Fe²⁺ is the catalyst needed to produce OH- radical in Fenton reaction and participates in ferroptosis (Dong et al., 2023).

Nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to alleviate liver oxidative damage and cell apoptosis by upregulating the expression of antioxidant and detoxification pathways. Han et al. (2023) found that after treating T. gondii-infected mice with cynaroside, the expressions of key proteins in the Nrf2/heme oxygenase-1 (HO-1) antioxidant pathway, including Nrf2, HO-1, NAD(P)H quinone oxidoreductase-1 (NQO-1) and glutamate-cysteine ligase (GCLC), were significantly increased. After treatment with cynaroside at doses of 100 mg/kg and 200 mg/kg, the expressions of these oxidative stress inhibitors were significantly upregulated. Moreover, after treatment with cynaroside at a dose of 50 mg/kg, the expressions of Nrf2, HO-1 and NQO-1 were also increased significantly. The activation of Nrf2/HO-1 pathway to protect cells from the harmful effects of oxidative stress is an adaptive response. When ROS increase, Nrf2 is activated and rapidly triggers the expression of antioxidant enzymes HO-1 and NQO-1 to exert cellular antioxidant functions (Xu et al., 2017).

De Stefano et al. (2021) further explored that cynaroside affected the cholesterol hydroxylation pathway, increased cholesterol levels and substantially reduced the levels of 7-α-hydroxycholesterol, 7-β-hydroxycholesterol and 7-ketocholesterol in the human keratinocyte model. These hydroxycholesterol is often found to be increased in many pathological situations, causing cytotoxic effects by inducing oxidative stress and dysfunction of organelles, such as mitochondria, lysosomes and peroxisomomes. In addition, cynaroside regulated the fatty acid hydroxylation pathway, leading to increased linoleic acid content and decreased contents of 2-hydroxypalmitate, 2-hydroxystearate and 2-hydroxydecanoate.

Obesity is a chronic metabolic syndrome with energy metabolism imbalance, characterized by abnormal accumulation of adipose tissue and glucolipoprotein metabolism (Schwab et al., 2014). The imbalance caused by obesity can lead to T2DM, MASLD, atherosclerotic cardiovascular disease, nephrotic syndrome and other chronic diseases (Li et al., 2023). According to the Global Burden of Disease Report released by the World Health Organization (WHO), as of 2023, 34.8% of the global adult population is overweight (BMI ≥ 25 kg/m²) and 14.1% meets the diagnostic criteria for obesity (BMI ≥ 30 kg/m²) (NCD Risk Factor Collaboration, 2024). Longitudinal epidemiological surveys revealed that the global adult obese population more than doubled between 1990 and 2022. In 2022, the total number exceeded 1 billion, accounting for about 12.5% of the global population (Jaacks et al., 2019). Clinical treatment of obesity is based on lifestyle improvement, including dietary structure modification and exercise therapy (Medina-Remón et al., 2018). However, the sustainability of behavioral interventions is often limited by patients’ compliance, which is prone to weight regain. In terms of drug treatment, orlistat (a pancreatic lipase inhibitor) reduces energy intake by reducing dietary fat absorption, while GLP-1 receptor agonists (such as selmegallutide) exert weight-loss effects through central appetite suppression and peripheral metabolic regulation (Perdomo et al., 2023). In addition, recently, the role of the gut microbe-host metabolic axis in obesity has become increasingly clear. The abundance changes of specific bacterial groups can affect SCFAs synthesis, bile acid metabolism, and intestinal barrier integrity, thus interfering in energy absorption and storage efficiency. For example, phenolamide compounds isolated from apricot pollen can ameliorate obesity-related inflammation by regulating gut flora composition (e.g., increasing the abundance of Bifidobacterium and Lactobacillus) and repairing abnormal metabolite profiles (Zhang et al., 2023). Fermented Tartary buckwheat extract showed dual regulatory potential, which could not only enhance glucose and lipid homeostasis, but also inhibit the release of proinflammatory factors and reverse hepatocyte steatosis (Yang et al., 2023).

Yang et al. (2025) established a obesity model fed by 1 week HFD in 6-week-old male C57BL/6J mice, and simultaneously gave them low dose (5 mg/kg), medium dose (50 mg/kg) and high dose (100 mg/kg) of cynaroside for 12 weeks. In the HFD group, the body weight, liver weight, adipose tissue weight of mice were significantly increased. In addition, obese mice had impaired glucose tolerance and increased steatosis and damage in hepatocytes. Cynaroside intervention significantly improved these phenomena, suppressed mouse weight gain, reduced TC, TG and LDL-C levels in serum, inhibited adipocyte hypertrophy and reduced the level of inflammatory factors (Yang et al., 2025). Gebhardt (1998) found that cynaroside, the active ingredient in C. scolymus extract, inhibited cholesterol biosynthesis in hepatocytes by inhibiting HMG-CoA activity through in vitro cell experiments. Azevedo et al. (2010) supplemented the relevant animal experiments. In their study, six-week-old healthy male Wistar rats were treated with 2 mg/kg ursolic acid or cynaroside for 7 consecutive days. By collecting and testing rat blood and liver samples, cynaroside was found to reduce TC and LDL-C levels. Ong et al. (2011) researched the effects of polyphenols-rich V. amygdalina extracts in a rat model of streptozotocin-induced diabetes and found that extract treatment not only reduced blood glucose and significantly reduced TG and TC levels in the serum of rats (18.2% and 41%, respectively). Analysis of the chemical composition of the extract using HPLC found that the active ingredient playing the main role was also cynaroside. Most of these studies have their limitations. Gebhardt et al. first found the lipid-lowering effect of cynaroside, but they gave a complex plant extract and did not detail the proportion of active ingredients. Azevedo et al. used a single component and supplemented animal experiments, but the number of animals used in this study was relatively small and the duration of the experiment was short to fully assess the long-term effects of cynaroside on lipid profiles. The study did not explore the exact pathway by which cynaroside affects lipid metabolism, nor did it compare it with existing anti-diabetic drugs. In contrast, Yang et al. conducted a more comprehensive study by using a single component for a longer period of time in animal experiments, comparing it with existing drugs to explore its potential mechanisms, and comparing the effects of cynaroside on insulin sensitivity or glucose tolerance tests and other organs.

Cynaroside can simulate endogenous estrogen and play an estrogen-like role to improve blood lipid profile, thus improving obesity. Ammar et al. (2016) established an ovariectomized rat model to explore the estrogenic activity of cynaroside. The animal experiment used 24 female Sprague Dawley rats weighing 100–140 g and randomized them into four groups with following treatments: normal control, bilateral oophorectomy, 17-β-estradiol (10 μg/kg body weight) and cynaroside (5 mg/kg body weight). Cynaroside was found to significantly reduce the TC, TG, LDL-C and TC/HDL-C ratio, and significantly increase the HDL-C level. At a dose of 5 mg/kg, it showed significant estrogenic activity and maintained normal uterine weight and plasma estradiol levels. Cynaroside significantly inhibited bone conversion markers such as bone-specific alkaline phosphatase (BALP), plasma osteocalcin (OCN), type I procollagen N-terminal peptide (PINP) and type II collagen C-terminal peptide (CTX-II).

MASLD has emerged as a prominent global health challenge due to its asymptomatic manifestations, high prevalence and potential intra and extrahepatic consequences, often concurrent with the prevalence of obesity and T2DM and is a major cause of liver-related morbidity and mortality (Anonymous, 2025). It is characterized by excessive hepatic lipid accumulation (liver steatosis), which can lead to inflammation (steatohepatitis) and progressive fibrosis (European Association for the Study of the Liver (EASL) et al., 2024). By 2021, the global prevalence of MASLD has reached 32.4% and shows a continuous upward trend (Tincopa and Loomba, 2024). This disease spectrum covers stages from early simple hepatic steatosis to metabolic-associated steatohepatitis (MASH), which can further progress to hepatocirrhosis and hepatocellular carcinoma (HCC) (Tincopa and Loomba, 2024). The severity of fatty liver disease is influenced by multiple factors, including genetic susceptibility, nutritional composition, obesity, insulin resistance, gut microbiome and a range of disease endocrine effectors. For the treatment of MASLD patients, it is recommended to base the approach on lifestyle changes and enhance the management of comorbidities, including weight loss, dietary modifications, physical exercise, and abstinence from alcohol. Resmetirom has histological efficacy for steatohepatitis and liver fibrosis with acceptable safety and tolerability. Currently, there are no targeted drug therapies for MASH in the cirrhosis stage, the treatment principles are similar to those for cirrhosis caused by other reasons, including metabolic adjustment medications, nutritional counseling, monitoring of portal hypertension and HCC, as well as liver transplantation for decompensated cirrhosis. Recent studies have found that cynaroside has a good improvement effect on MASLD, which has been confirmed through in vitro and in vivo experiments.

Yixiao et al. (2023) established a mouse model of HFD-induced MASLD in eight-week-old male C57BL/6 mice, and the groups were control group, HFD group, low dose Sanren Tang (crude drug 1.09 g/mL, 20 mL/kg body weight) group, high dose Sanren Tang (crude drug 2.18 g/mL, 20 mL/kg body weight) group and obe cholic acid (10 mg/kg) group. The animal study induced MASLD in mice by a 13-week HFD, followed by 3 weeks of intervention with Sanren Tang (a characteristic component of Herba Lophatheri) and obe cholic acid. They also verified that cynaroside as the main active component of Sanren Tang improved liver histology and fat deposition in MASLD mice, decreased insulin resistance index, NAFLD activity score (NAS) and serum alanine aminotransferase (ALT) and liver TG levels. RNA sequencing was performed and the liver transcriptome was analyzed, revealing that this improvement was associated with retinol metabolism, cytokine-cytokine receptor interaction, and PPARγ signaling. This study is a controlled study with effective control of experimental variables, but there are still some limitations. The relatively small sample size of the study, and the complex identification of SRT components, may not fully explain all of its pharmacological effects, which may limit the generalizability of the results.

Meng et al. (2023) evaluated the efficacy of cynaroside in liver fibrosis in a HFD-induced MASH mouse model. The model was developed by inducing lipotoxic liver injury in BKS-db males mice (Jingle Biotech) fed by SYGR01 HFD (4.13 kcal/g) for 4 weeks, and the mice were divided into blank control group, MASH model group, cynaroside (20 mg/kg) group and positive control pioglitazone group. The results showed that cynaroside alleviated liver steatosis (45% less oil red staining area) and reduced F4/80 marked inflammatory cell infiltration (60% less than model group). In addition, Meng et al. verified the role of cynaroside in the regulation of fibroblast growth factor receptor 2 (FGFR2)/TGF-β signaling cascade in the development of liver fibrosis (Meng et al., 2023). Cynaroside blocked the activation and development of liver fibrosis by inhibiting the overexpression of FGFR2 and the excess of basic fibroblast growth factor (bFGF), thus reducing hepatic stellate cell (HSC) activation and collagen secretion in hepatocytes (Sato-Matsubara et al., 2017; Wang et al., 2020). In addition, cynaroside reduced α-SMA (45% reduction) and Collagen I (50% reduction) expression in LX-2 cells and truncated the paracrine activation loop between HSC and hepatocytes (Meng et al., 2023). The study design is reasonable and comprehensive, including both cell experiments and animal experiments as well as molecular docking and molecular dynamics simulation. However, there is a lack of comprehensive molecular-level explanation for the mechanism of cynaroside in treating liver fibrosis. Although cynaroside has shown inhibitory effect on FGFR2 in vitro and animal models, its pharmacokinetic and pharmacodynamic characteristics in human body need to be further studied.

Jia et al. (2022) found that Mailuoning oral liquid (7.8 mL/kg or 23.4 mL/kg, for 4 weeks) effectively alleviated lipid deposition by regulating PGC-1α/PPARα signaling pathway in MASLD by using methionine and choline deficient (MCD) diet-induced MASH for 2 weeks in mice. PPARα is a member of the ligand-induced transcription factor nuclear receptor family, crucial for regulating various metabolic pathways, including lipid metabolism, bile acid and cholesterol metabolism, as well as inflammation. The transcriptional activation of PPARα is regulated by multiple co-activators, with PGC-1α being the primary reported co-activator involved in activating PPARα. In this study, Mailuoning oral liquid increased the nuclear accumulation of PPARα and the expression of PGC-1α in the livers of MCD diet-fed mice, and also enhanced the expression of multiple downstream genes of PPARα (Pawlak et al., 2015). Through HPLC, cynaroside was found to be the active component of Mailuoning oral liquid that significantly reduced lipid accumulation in hepatocytes stimulated by non-esterified fatty acids (Jia et al., 2022).

Zhu et al. (2021) established an in vitro model of MASH induced by palmitic acid (PA) and found that cynaroside could stimulate hepatocyte regeneration by activating STAT3 pathway. In their study, LO2 cells (human hepatocyte cell line) and primary hepatocytes isolated from C57BL/6J mice were treated with PA (500 μM) for 48 h to induce steatosis. Upon addition of cynaroside (20 μM), the PA induced proliferation inhibition was reversed (MTT absorbance returned to 85% of control), and the STAT3 pathway increased cyclin D1 and c-myc by increasing phospho-STAT3 levels 3.2-fold (Zhu et al., 2021). The cyclin D1 and c-myc positively regulated cell cycle progression and decreased the expression of the cell cycle progression inhibitor p21 (Lu et al., 2018). Musolino et al. (2022) also demonstrated the potential anti-inflammatory and reduced lipid accumulation of O. europaea L. folium using an in vitro model of MASH. The main polyphenolic compounds in the Olea europaea leaf extract include cynaroside and oleuropepein (Guinda et al., 2015). A rat liver tumor cell line (McA-RH7777) was exposed to oleic acid to mimic the effects of lipid accumulation and inflammatory status. Using nile red and oil red O staining to detect lipid accumulation, and cytokines bioplex assay to assess inflammation, it was found that olive leaf extracts at concentrations of 25, 50 and 100 μg/mL were able to reduce intracellular lipid content and thereby combated the intracellular inflammatory state (Musolino et al., 2022). Neither study included in vivo experiments, and the cell models and experimental conditions used in the studies may not fully simulate the complex physiological environment in vivo.

Diabetes mellitus (DM) is a kind of chronic systemic disease with glucose metabolism disorders as the core, which is listed as a key disease for global public health prevention and control by the WHO (Evaluation I.f.H.M.a, 2024). According to its pathological characteristics, DM can be divided into type 1 diabetes (T1DM) and T2DM. T1DM is characterized by absolute insulin deficiency caused by the autoimmune destruction of islet β-cells, while T2DM is attributed to the relative insufficiency of insulin secretion and mainly caused by insulin resistance (Sun et al., 2022). In recent years, the global prevalence of T2DM has increased exponentially, and its disease burden is closely related with obesity, sedentary lifestyle and genetic susceptibility (Sun et al., 2022). T2DM is commonly associated with abnormal lipid metabolism and considered a major risk factor for premature development of atherosclerosis and cardiovascular complications (Saltiel and Kahn, 2001; Biddinger and Kahn, 2006). Long-term imbalance in blood glucose homeostasis can cause multiple organ damages through various metabolic routes. Microvascular complications include diabetic retinopathy, peripheral neuropathy and diabetic nephropathy. Macrovascular lesions significantly increase the risk of atherosclerosis, myocardial infarction and stroke (Singh et al., 2025). The treatment of T2DM is based on lifestyle intervention, combined with biguanides, sodium-dependent glucose transporters 2 (SGLT2) inhibitors, and GLP-1 receptor agonists to improve glycemic control. Recently, a number of studies have shown that natural ingredients such as cynaroside also have good hypoglycemic effects (Xu et al., 2018; Majety et al., 2023). Research of natural extracts and compounds containing cynaroside have shown potential in addressing diabetic symptoms and complications (Table 2).

Cynaroside effectively reduces postprandial hyperglycemia in T2DM mice by inhibiting the activity of α-glucosidase and α-amylase (Kim et al., 2000; Asghari et al., 2015). The hydroxyl substitution in the B ring of the compound and the sugar moiety in the A ring are effective factors for the inhibitory activity of flavonoids. Then Orhan et al. confirmed this view with a STZ-induced diabetes model (Orhan et al., 2016). Shojaeifard et al. (2023) selected 50 different samples of 32 Salvia species and measured their inhibitory activity against α-glucosidase at three different concentrations (250, 500, and 1,000 μg/mL) and compared them with the positive control drug acarbose. Research has found that the inhibitory activities of Salvia multicaulis, Salvia santolinifolia, Salvia dracocephaloides, and Salvia eremophila were stronger than those of acarbose (p < 0.05), with their IC50 values ranging from 26.23 to 92.35 μg/mL. Through phytochemical analysis, eight common α-glucosidase inhibitors were isolated, including cynaroside, luteolin-7-O-glucuronide, apigenin-7-O-glucoside, apigenin-7-O-glucuronide, hispidulin-7-O-glucuronide, hispidulin-7-O-glucoside, rosmarinic acid and carnosic acid. The content of these compounds in active species ranges from 1.5% to 95.0%, with cynaroside detectable in most α-glucosidase inhibitor species.

Cynaroside increases liver glycogen content by inhibiting liver G-6-Pase activity, and can also stimulate skeletal muscle GLUT4 expression and glucose uptake by activating PPARγ pathway and increase muscle glycogen content. Ong et al. (2011) established a single dose of STZ (65 mg/kg, for 5 days) induced diabetic animal model and identified cynaroside as the active ingredient in the ethanol extract of V. amygdalina STZ induced diabetic rats were randomly selected and categorized into three groups (vehicle, 500 mg/kg metformin and 400 mg/kg V amygdalina) for a 28-day chronic study monitoring body weight, food and water intake, detecting insulin, TG, TC levels and hepatic G-6-Pase activity. The experimental results showed that fasting blood glucose decreased significantly after 28 days of treatment (32.1%), histology showed less pancreatic cell damage (no vacuoles and less granulation), more functional cells, GLUT4 expression in skeletal muscle (24%) and transposition to the plasma membrane (35.7%), and inhibited the activity of key hepatic gluconeogenic enzyme G-6-Pase (40% inhibition). This conclusion was also confirmed experimentally by Ighodaro and Akinloye (2017). Similarly, diabetes was induced in experimental animals via single intraperitoneal dose (55 mg/kg) of freshly prepared STZ. Sapium ellipticum was evaluated at 400 and 800 mg/kg of body weight against metformin (12 mg/kg). Treatments were done orally, twice daily at 8 h interval for a period of 21 days. Studies of the active ingredient cynaroside of S. ellipticum leaf extract revealed that S. ellipticum significantly reduced fasting blood glucose levels by 46.5% and 44.4% (doses of 400 and 800 mg, respectively), hepatic and skeletal muscle glycogen by 27.06% and 12.55% (doses of 800 mg), and increased plasma and pancreatic insulin content (31.77% and 52.34%, respectively) (Ighodaro and Akinloye, 2017). The limitation of Ong et al. study is that changes in insulin levels may be a confounding factor, and cynaroside leads to a slight increase in insulin levels, which in turn can increase GLUT 4 translocation and glycogen synthesis, while inhibiting gluconeogenesis enzymes such as G6Pase. Ighodaro et al. did not isolate and purify the bioactive compounds in the extract of Sapium ellipticum leaves, nor did they evaluate its long-term therapeutic effects and potential toxicity.

Due to the chronic elevation of blood glucose levels, long-term vascular complications of diabetes occur, including “microvascular diseases” (caused by damage to small vessels, such as retinopathy, nephropathy, and nerve damage) and “macrovascular diseases” (caused by damage to arteries, including acute cardiovascular and cerebrovascular diseases). The organ failure caused by diabetic complications is the most destructive consequence of diabetes and the primary cause of death in diabetic patients (Forbes and Cooper, 2013). It is reported that dyslipidemia is particularly important for the occurrence of neuropathy, retinopathy and nephropathy, lipid reduction can significantly improve diabetes complications and their prognosis (Davis et al., 2008). In T2DM, a large number of peripheral neuropathy cases (up to 10%–20% of patients) appear at the time of diagnosis (Charles et al., 2011). Increased lipid levels and body mass index may exacerbate the risk of diabetic neuropathy (Sone et al., 2005).

Aldose reductase (ALR) is the rate-limiting enzyme in the polyol pathway and its main role is to reduce glucose to whole sugar and participate in the regulation of the intracellular redox system (Gupta, 2024). Increased sorbitol production in many tissues does not readily diffuse through the cell membrane, and the intracellular accumulation of sorbitol has been associated with chronic complications of diabetes, such as cataracts, neuropathy and retinopathy (Sone et al., 2005). Glycoification is a non-enzymatic browning reaction caused by the amino-group reaction between reducing sugars and amino groups of proteins or lipids, which leads to the chemical modification of tissue proteins, known as advanced glycosylation end products (AGEs), leading to the dysfunction of proteins (Irani et al., 2014). Moreover, both diabetes and aging are associated with the accumulation of AGEs in tissues, increased oxidative stress and decreased antioxidant status. Complex fluorescent AGE molecules formed during the Maillard reaction can lead to protein cross-linking and promote the development and progression of diabetic complications, such as peripheral neuropathy, cataract, impaired wound healing, vascular injury, arterial wall sclerosis, and reduced myocardial compliance (Ott et al., 2014).

Plioukas et al. (2016) found that cynaroside inhibited the activity of ALR2. Since ALR is one of the pathogenic factors of diabetes, this study evaluated the inhibitory ability of cynaroside on ALR and verified its potential to combat long-term complications of diabetes. The antioxidant capacity of the above ground extract of Tephrosia humilis was assessed by DPPH radical and Co (II)/EDTA-induced chemiluminescence tests. The inhibitory activity of the extract on ALR2 and ALR1 was evaluated using partially purified mouse lens ALR2 and mouse kidney ALR1. Experimental results indicated that all extracts showed significant antioxidant capacity, and phytochemical analysis revealed that the active components in the extract contained various flavonoid compounds, including cynaroside (Plioukas et al., 2016). Hwang et al. (2019) assessed the inhibitory activity of ALR, late AGEs and the scavenging activity of DPPH radicals from 22 Peruvian plant extracts, and found cynaroside was the active ingredient to inhibited the activity of ALR. These two studies provide preliminary evidence of the antioxidant and aldose reductase inhibitory properties of cynaroside, but do not address the effects of cynaroside in vivo models, limiting a comprehensive assessment of its potential medicinal value in plants.

Diabetic vascular complications are early characterized by endothelial dysfunction, which is characterized by enhanced oxidative stress and inflammation, reduced bioavailability of NO and impaired endothelium-dependent vasodilatation. Acetylcholine-induced vasodilatation occurs through the Ach/JAK2/IRS-1/PI3K/Akt/eNOS pathway, and this pathway is disrupted in diabetic conditions (Huang et al., 2018). Moreover, in diabetic patients, microvascular injury occurred earlier than large vessel injury (Shi and Vanhoutte, 2017). Li et al. (2020a) suggested that cynaroside, the active component of Coreopsis tinctoria Nutt. flower, has a role of diabetic endothelial protection and may be related to its effect on the JAK2/IRS-1/PI3K/Akt/eNOS pathway, the associated oxidative stress and inflammatory response. Vascular function was assessed by examining endothelium-dependent vasodilatation and tail artery pressure in rat mesenteric arteries using a HFD and STZ-induced diabetes model. The results indicated that the treatment of cynaroside significantly improved endothelium-dependent vasodilation in the mesenteric arteries of diabetic rats, with a maximum relaxation of 79.82% in the control group and 91.87% in the extract-treated group (p < 0.01). The extract treatment also reduced tail artery pressure of rat, with both systolic and mean arterial pressure decreased (p < 0.05). A high glucose-induced human umbilical vein endothelial cells model was established in vitro, and the expression of IRS-1, Akt, and eNOS increased p-IRS-1Ser307, p-AktSer473, and p-eNOSSer1177 and decreased the expression of NOX4, TNF-α, IL-6, sVCAM, sICAM, and NF-κB (p < 0.01). Although Li et al. explored the mechanisms of action of active ingredients through in vitro experiments and animal models, their research lacks in-depth studies on the pharmacokinetics and pharmacodynamics of these components in the human body. The randomized controlled trials did not provide a detailed comparison of the effects of glucose at different concentrations and treatment durations on cells, which may result in an incomplete understanding of the mechanisms of endothelial cell damage induced by hyperglycemia.