DOI:http://doi.org/10.65281/736509
Jiangyue Liu123,Maimaititusun Yalikun13*,Wenjing Chen14*,Jingcheng Dong124*
1 Institutes of Integrative Medicine, Fudan University, Shanghai 200032, China;
2 School of Pharmacy, Fudan University, Shanghai 200433, China;
3 Kashgar People’s Hospital, Kashgar 844099, Xinjiang, China;
4 Huashan Hospital, Fudan University, Shanghai 200040, China;
*Corresponding authors:
Jingcheng Dong
E-mail address: jcdong2004@126.com
Address: 131 Dong’an Road, Xuhui District, Shanghai 200032, China
Tel.: +86-21-52888301
Fax: +86-21-52888265
Maimaititusun Yalikun
- mail address:mtyalkun@126.com
Address: 131 Dong’an Road, Xuhui District, Shanghai 200032, China
Tel.: +86-21-52888301
Fax: +86-21-52888265
Wenjing Chen
E-mail address: 15211280011@fudan.edu.cn
Address: 131 Dong’an Road, Xuhui District, Shanghai 200032, China
Tel.: +86-21-52888301
Fax: +86-21-52888265
Abstract
Ethnopharmacological Relevance
Carthamus tinctorius L. (safflower) is pivotal in ethnomedicines (Chinese, Mongolian, Uyghur), traditionally used for promoting blood circulation and relieving stasis, with cross-ethnic therapeutic applications.
Aim
To synthesize safflower’s botanical traits, chemical components, pharmacological effects, and safety, supporting its ethnopharmacological translation.
Materials and Methods
A narrative review of literature on safflower’s domestication, morphology, genetics, chemistry, pharmacology, safety, and pharmacokinetics.
Results
Safflower was domesticated ~4,500 years ago in the Fertile Crescent, with adaptive genetic variations; >200 compounds (e.g., hydroxysafflor yellow A(HSYA）, kaempferol) were isolated. It has anti-inflammatory, antioxidant, cardiovascular, antitumor activities; seed oil modulates lipid metabolism/microbiota. Key components show good safety, with pharmacokinetic gender differences.
Conclusions
Safflower’s ethnopharmacological value is validated by modern research, warranting further omics and stress resistance studies to advance its use in functional foods and new drugs.
Key words:Carthamus tinctorius L.;botanical characteristics; chemical composition; pharmacological effects.
- Introduction
Carthamus tinctorius L.(0000024004), commonly known as Safflower, has its pharmacologically active part in traditional medicine as the tubular flowers devoid of ovaries, which belongs to the genus Carthamus in the family Asteraceae. According to the “Chinese Pharmacopoeia” (2020 edition), safflower has a surface that is red-yellow or red, emits a slight fragrance, and possesses a mildly bitter taste. It is known for its effects in promoting blood circulation, regulating menstruation, dispersing blood stasis, and alleviating pain (National Pharmacopoeia Committee, 2020). Modern studies have demonstrated that safflower exhibits a variety of biological activities, including anti-inflammatory, antioxidant, anti-tumor, and analgesic effects (Bai et al., 2025; Fu et al., 2022), and it has been extensively utilized in the treatment of cardiovascular and cerebrovascular diseases, as well as gynecological disorders (Delshad et al., 2018; Zhang et al., 2016). Furthermore, as an oilseed crop, safflower seeds are rich in various unsaturated fatty acids, including linoleic acid, palmitic acid, and oleic acid. Recent research has confirmed that safflower seed oil not only possesses antioxidant, anti-inflammatory, and skin barrier protection properties but also acts as an excellent skin permeation agent with superior permeability, making it suitable for skin wound repair and other applications. Additionally, the antibacterial effects of safflower seed extract can significantly accelerate the skin wound healing process (Chang et al., 2025; Grytten et al., 2025; Jaradat et al., 2024; Kurt et al., 2025; Li et al., 2025; Wu et al., 2025; Zhang et al., 2025).
Safflower is extensively utilized in the traditional medicine practices of various ethnic groups and countries, including Indian Ayurvedic medicine (Charaka, 1), Chinese traditional medicine, particularly in Uyghur medicine (Health Department of Xinjiang Uyghur Autonomous Region, 1985), and the Mongolian medical system. It serves as a fundamental herb in formulations aimed at regulating Qi and blood, as well as promoting blood circulation to alleviate stasis (Bao Xiufang et al., 2024).
Another traditional medicinal herb, saffron, is often confused with safflower due to their similar names. The scientific name of saffron is Crocus sativus L.(0000788844), which belongs to the genus Crocus in the family Iridaceae. The medicinal part of saffron specifically refers to the stigma of the flower (Xinjiang Uygur Autonomous Region Health Department, 1985). Modern research and traditional applications indicate that the primary efficacy of saffron lies in its ability to regulate neurotransmitter activity and improve mood (Matraszek-Gawron et al., 2022). Thus, saffron significantly differs from safflower in terms of plant classification, medicinal parts, and efficacy; this article will not elaborate on these differences further.
Fig.1.This diagram illustrates the botanical characteristics of Carthamus tinctorius L., presenting its overall plant structure, leaf and seed structure, flower characteristics, as well as growth stages and variations under different meteorological conditions.
Fig.2.This picture shows a comparison of the flower forms of two plants, Carthamus tinctorius L. (Safflower) and Crocus sativus L. (Saffron Crocus).some botanical images of the genus Gentiana were obtained from PPBC.(https://ppbc.iplant.cn/)
2.Botanical Characteristics
2.1 Historical Cultivation and Domestication
The history of safflower cultivation and domestication dates back to ancient times. It is widely accepted that safflower was domesticated approximately 4,500 years ago in the Fertile Crescent, which refers to the fertile lands of the river valleys in Western Asia and North Africa, from its presumed wild ancestor, Carthamus palestinus (Yildiz et al., 2022). Phylogenomic studies utilizing genotyping sequencing have confirmed that Palestinian safflower is the closest relative and sole ancestral variety of safflower, indicating that the Levant region, encompassing the eastern Mediterranean coast including areas of Syria, Lebanon, Israel, and other countries, served as the site of safflower domestication (Sardouei-Nasab et al., 2023).
The analysis of global safflower germplasm resources provides a crucial foundation for understanding its genetic diversity and population structure. A study employing DArTseq technology on 89 safflower germplasm resources revealed that these germplasms can be classified into three distinct groups, with diversity patterns showing a weak correlation to their geographical origins (Jaradat et al., 2024). Another study utilizing Peroxidase Gene Polymorphism (POGP) markers on 131 safflower germplasm resources found that germplasms from Asian countries, including China, Afghanistan, Turkey, Iran, and Pakistan, exhibited genetic similarity and could be categorized into a single group, while germplasms from the Fertile Crescent region formed a separate group. This finding further supports the notion that the Fertile Crescent is the origin of safflower domestication (Yildiz et al., 2022).
Currently, China has successfully completed chromosome-level genome sequencing for two safflower varieties from distinct regions: “Yunhong 1” and “Anhui 1.” The results reveal that these regional safflower varieties exhibit genetic differences in pathways related to fatty acid biosynthesis, circadian rhythm, and flavonoid biosynthesis. These genetic variations may be linked to the adaptation of safflower to local environments throughout its domestication process (Liu et al., 2025).
The domestication of safflower may have been influenced by its favorable traits, with oil-rich seeds being one of the most significant characteristics. In recent decades, the high oleic acid trait has emerged as a research hotspot, controlled by the partially recessive allele ol at a single locus, OL. DNA sequence data and Southern blot analysis have revealed that the FAD2-1 gene in safflower originated from ancient hybridization and introgression with its wild relative, Carthamus palaestinus, while the FAD2-1Δ gene evolved relatively later based on this foundation (Rapson et al., 2015).
Understanding the historical cultivation and domestication of safflower is crucial for its genetic improvement and utilization. This foundational knowledge not only facilitates the exploration of safflower’s genetic diversity and evolutionary history but also strongly supports modern breeding efforts. Such efforts aim to develop safflower varieties with higher oil content, enhanced disease resistance, and improved adaptability to diverse environments.
2.2 Morphological Characteristics
The safflower plant exhibits distinctive morphological characteristics, including a thorny stem, amplexicaul and alternate leaves, and a capitulum adorned with spiny involucral bracts at the apex (Baljani et al., 2016). In a study focused on screening indicators for oil content and fatty acid composition in safflower, researchers identified correlations between various phenological and morphological traits and the oil content of safflower. Specifically, the hull rate, grain length-to-width ratio, and plant height emerged as the most promising screening indicators for enhancing oil content, while the number of grains per capitulum was deemed the optimal yield component for increasing yield without compromising oil content. These morphological characteristics can serve as significant reference indicators in breeding efforts, facilitating the selection of safflower varieties with superior traits related to oil content (Cerrotta et al., 2020).
External environmental factors can significantly influence the morphological characteristics of safflower. In a study investigating the effects of drought on the natural pigments and bioactivity of safflower, researchers subjected two safflower varieties, “Jawhara” and “104”, to varying levels of water deficit. The results indicated that a 50% water deficit significantly inhibited the growth of safflower plants. Furthermore, drought impacted the content of phenolic compounds and carotenoids in safflower flowers. Under the 50% water deficit condition, both varieties exhibited a notable increase in phenolic acids, particularly gallic acid, while the “Jawhara” variety demonstrated a higher total carotenoid content at this level of water deficit. Although the study did not directly explore whether the changes in the chemical composition of safflower due to drought are related to alterations in its morphological appearance, it can be inferred that such changes in chemical composition are likely accompanied by modifications in the plant’s morphology (Salem et al., 2014).
Understanding the relationship between environmental factors and the morphological characteristics of safflower is crucial for optimizing cultivation conditions and ensuring high-quality production. This knowledge can aid growers and breeders in adapting to varying environmental conditions and in formulating effective strategies to maintain or enhance both the yield and quality of safflower.
2.3 Genetic Diversity and Breeding
Research on the genetic diversity of safflower serves as a critical foundation for breeding and improvement efforts. In a study involving 105 distinct safflower varieties, 18 pairs of simple sequence repeat (SSR) markers were employed to detect polymorphism among these varieties. The results indicated that the average gene diversity was 0.45, the average heterozygosity was 0.37, and the average polymorphism information content (PIC) was 0.39. Adjacency clustering analysis revealed that these populations could be categorized into six major groups, effectively distinguishing wild germplasm resources from cultivated varieties (Mokhtari et al., 2018). Similarly, the research team examined 11 oil-related quantitative traits and utilized 50 pairs of insertion-deletion (InDel) markers to evaluate the diversity of 605 safflower germplasm resources, constructing a core germplasm resource library comprising 214 varieties and identifying 47 genes associated with lipid biosynthesis (Fan et al., 2023). Furthermore, the team employed Sequence-Related Amplified Polymorphism (SRAP) markers and Start Codon Targeted (SCoT) polymorphism techniques to conduct genotypic studies on 100 safflower varieties from various global regions. The studies revealed significant genotypic differences among safflowers from different regions, and even within populations from the same region, a high level of genotypic variability among individuals was observed (Golkar and Mokhtari, 2018). Research on the genetic diversity of safflower provides essential biological insights for the enhancement of safflower varieties.
A joint scaling test on the genetic regulation of carthamin and carthamidin in safflower revealed that in two different hybrid combinations, the additive effect (a), additive × additive epistasis (aa), and additive × dominance epistasis (ad) significantly influenced the genetic control of these pigments (Golkar, 2018). The narrow-sense heritability of these two traits was moderate at 48% and lower at 17%, respectively, thereby providing a foundation for developing breeding strategies aimed at enhancing the content of these pigments in safflower (Zhao et al., 2024). Furthermore, another research team successfully expressed recombinant human fibroblast growth factor 10 (rhFGF10) by constructing a plant expression vector through genetic recombination technology and introducing it into safflower. This achievement in genetic engineering offers a novel approach for the low-cost, safe, and efficient production of rhFGF10 to meet its demand in basic research and clinical applications (Huang et al., 2017).
Fig.3.Fig.4.The pictures illustrate the cultivation and breeding strategies for Carthamus tinctorius (safflower) using an integrated genomics approach, covering aspects such as genetic diversity, breeding strategies, environmental adaptability, and marker-assisted selection.
- Chemical Composition
Safflower, a natural medicinal herb, is rich in chemical components and exhibits a wide range of biological activities, making it a prominent topic in contemporary natural product research. To date, over 200 compounds have been isolated from safflower, including quinone chalcones, flavonoids, spermidines, alkaloids, polyacetylenes, organic acids, and sesquiterpenes (Zhang et al., 2024). Additionally, multiple unsaturated fatty acids, such as linoleic acid, palmitic acid, oleic acid, and stearic acid, have been isolated and identified from safflower seed oil (Dong et al., 2024). Recent advancements in separation technologies have provided critical support for the precise identification and application of active ingredients in natural medicines. Research into the efficacy and mechanisms of action of these active ingredients has yielded new insights for disease treatment and the development of novel drugs.
3.1 Purification and Identification Techniques
Among the various active components in safflower petals, quinone chalcones and flavonoids represent the two most prominent classes of compounds. HSYA and kaempferol are specifically recognized in the Chinese Pharmacopoeia as quality control markers for safflower (National Pharmacopoeia Committee, 2020). This designation arises from their role as the material basis for the traditional efficacy of safflower (Shahbaz et al., 2023; Shi et al., 2025; Wang et al., 2025) and their stable, measurable content. The levels of these compounds serve as direct indicators of the quality of safflower medicinal materials and preparations. A mature technical system has been established for the separation and analysis of these two quality control components (Zhou et al., 2025), which includes matrix solid-phase dispersion (MSPD) extraction technology combined with high-performance liquid chromatography-diode array detection (HPLC-DAD) and ultra-performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UPLC-Q-TOF-MS) techniques. These methods are essential for identifying the main compounds present in safflower. In this study, silica gel serves as the dispersive adsorbent, utilized at a mass ratio of 3:1 relative to the sample. An elution solvent composed of 10 mL methanol-water (in a volume ratio of 1:3) is employed. The optimized matrix solid-phase dispersion method exhibits excellent linearity (r² ≥ 0.9992) and precision (relative standard deviation RSD ≤ 3.4%) for HSYA and kaempferol. The detection limits are determined to be 35.2 ng/mL and 14.5 ng/mL, respectively, with recoveries ranging from 92.62% to 101.7% and relative standard deviations between 1.5% and 3.5%. These results fulfill the criteria for accurate quantification of trace components (Hong et al., 2015). Additionally, the researchers successfully isolated 6-hydroxykaempferol-3-O-β-D-glucoside-7-O-β-D-glucuronide(a novel flavonol glycoside) , from safflower, alongside eight known flavonoids and three known quinone chalcones (Xie et al., 2016).
SPS is a significant water-soluble component of safflower (Jiang et al., 2025). Homogeneous sugars, defined as “pure and structurally characterized” carbohydrate substances, address the gap in the structure-function relationship of natural sugars, which are predominantly heterogeneous mixtures (Nomura et al., 2022). Current extraction techniques primarily include solvent extraction, ultrasound-assisted extraction, and ultrafine grinding-assisted ultrasound extraction. To date, 17 homogeneous sugars have been isolated from safflower, comprising 13 neutral polysaccharides and 4 acidic polysaccharides. The analytical methods for polysaccharide structure identification are quite diverse. In addition to traditional chemical techniques such as partial acid hydrolysis, periodate oxidation, Smith degradation, and methylation analysis, chromatography, spectroscopy, and mass spectrometry are also core technologies employed (Li et al., 2025; Wang et al., 2023; Wu et al., 2021).
The currently prevalent extraction techniques for safflower seed oil encompass hydraulic pressing, continuous pressing (screw pressing), and Soxhlet extraction. All these methods necessitate the prior dehumidification of safflower seeds. In hydraulic pressing, the pre-treated safflower seeds are placed in the equipment and subjected to a pressure of 10 MPa to extract the oil. In continuous pressing, an electric motor drives a screw press that continuously compresses the pre-treated safflower seeds for oil extraction. Soxhlet extraction utilizes solvents, such as n-hexane, to extract oil from ground safflower seeds. Among various extraction methods, Soxhlet extraction exhibits the highest oil extraction efficiency, reaching up to 32.49% (Deviren and Aydin, 2023). Safflower seed meal, the solid by-product obtained after pressing the seeds of *Carthamus tinctorius* L. for oil extraction, has been subjected to high-speed counter-current chromatography (HSCCC) for the preparation, separation, and purification of N-feruloylserotonin (NF) and N-(p-coumaroyl)serotonin (NP). Following the determination of the partition coefficients of the target compounds in various biphasic solvent systems, researchers selected a biphasic solvent system comprising chloroform, methanol, and 0.1 mol/L hydrochloric acid (in a volume ratio of 1:1:1) for HSCCC separation. From a crude sample weighing 40 mg, 7.5 mg of N-feruloylserotonin and 6.9 mg of N-(p-coumaroyl)serotonin were successfully isolated, achieving purities of 98.8% and 97.3%, respectively. The structures of the isolated compounds were confirmed using hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) techniques (Zhang et al., 2015). The safflower seed coat extract (SCE) was obtained through solvent extraction combined with extraction and rotary evaporation techniques. Specifically, the components in the safflower seed coat were extracted using ethanol, followed by filtration and rotary evaporation to eliminate the ethanol. The residue was then dissolved in ethyl acetate and subjected to rotary evaporation again to yield a dry substance. Subsequently, the dry substance was dissolved in methanol, washed, and evaporated to a constant weight, ultimately yielding the target extract, which primarily contains coumaroyl-5-hydroxytryptamine CS and feruloyl-5-hydroxytryptamine (Wan et al., 2025).
These extraction and analysis techniques are crucial for obtaining high-purity safflower compounds and for gaining a deeper understanding of their chemical properties. Furthermore, they provide essential support for ongoing research into the pharmacological activities and potential applications of safflower compounds.
| hydroxysafflor yellow A | kaempferol | quercetin | N-feruloylserotonin | N-(p-coumaroyl)serotonin |
| gallic acid | linoleic acid | oleic acid | palmitic acid | stearic acid |
| Carthamin | Chlorogenic acid | Isorhamnetin | Caffeic acid | Luteolin |
Table.1.Chemical Compositions
3.2 Pharmacological Effects
Traditional Chinese Medicine theory posits that safflower facilitates blood circulation and alleviates blood stasis (National Pharmacopoeia Commission, 2020), making it effective in treating various ailments associated with poor qi and blood circulation as well as blood stasis obstruction. Furthermore, contemporary research highlights safflower’s anti-inflammatory, antioxidant, cardiovascular protective, and anti-tumor properties.
3.2.1 Anti-inflammatory activity
Among the various active components of safflower, HSYA and kaempferol are notable representatives exhibiting significant anti-inflammatory activity. A research team demonstrated through in vivo and in vitro experiments that HSYA reduces the expression of inflammatory factors IL-1β, IL-6, and TNF-α by inhibiting the positive feedback loop between Lipocalin-2 (LCN2) and the JAK2/STAT3 pathway in astrocytes, thereby alleviating neuroinflammatory damage (Song et al., 2025). Furthermore, another team confirmed that HSYA inhibits the Piezo1-YAP/JNK signaling pathway by binding to Piezo1, resulting in decreased levels of inflammatory factors TNF-α, IL-1β, and IL-6 (Zhang et al., 2025). Additional in vitro experiments revealed that HSYA activates the phosphorylation of TNF-α converting enzyme (TACE), promoting the shedding of tumor necrosis factor receptor 1 (TNFR1) from the surface of arterial endothelial cells, leading to the formation of soluble sTNFR1. This process inhibits TNFR1-mediated phosphorylation and degradation of IκBα, as well as the nuclear translocation of NF-κB p65, ultimately reducing the expression of the inflammatory factor ICAM-1 and the adhesion of macrophages to endothelial cells, effectively suppressing TNF-α-induced inflammatory responses (Wang et al., 2016). Moreover, a research team found through in vitro experiments that HSYA can inhibit the phosphorylation of IκBα and the binding of the NF-κB p65 subunit to DNA induced by lipopolysaccharide, thereby exerting anti-inflammatory effects. In vivo and in vitro studies have shown that kaempferol alleviates lung injury in septic mice and inhibits the inflammatory response of human pulmonary microvascular endothelial cells (HPMVEC) induced by lipopolysaccharide (LPS). The mechanism involves the inhibition of SIRT5-mediated desuccinylation of SRPK1, which promotes the stability of the SRPK1 protein. These findings suggest a novel direction for the treatment of sepsis-related acute lung injury (Zhang et al., 2025). Additionally, another study investigated the effects of kaempferol in a dextran sulfate sodium (DSS)-induced ulcerative colitis mouse model, revealing that kaempferol alleviates symptoms of DSS-induced colitis in mice and mitigates colonic damage. The anti-colitis activity of kaempferol can be attributed to its inhibition of the LPS-TLR4-NF-κB inflammatory pathway (Qu et al., 2021).
3.2.2 Antioxidant properties
Animal studies have demonstrated that HSYA can enhance the mRNA levels and enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the liver tissues of SD rats suffering from alcoholic liver injury. Additionally, HSYA reduces the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), thereby ameliorating liver injury in these rats (He et al., 2015). Furthermore, another study employing both in vivo and in vitro experiments revealed that HSYA exerts a neuroprotective effect on rats with cerebral ischemia-reperfusion injury (CIRI). This neuroprotective effect is partially attributed to its enhancement of tissue antioxidant capacity and reduction of protein oxidation, which may occur through a combined process of scavenging ONOO- and inhibiting protein carbonyl formation (Zhao et al., 2024).
The antioxidant effect of kaempferol involves multiple molecular mechanisms (de Oliveira, 2025). Studies have demonstrated that kaempferol can restore the activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes, stabilize mitochondrial membrane potential, and reduce ROS leakage resulting from mitochondrial dysfunction in motor and cortical neurons of human C9ORF72-ALS patients, as well as in the C9-500 mouse model (Pilotto et al., 2025). Both in vitro and in vivo experiments have shown that kaempferol significantly inhibits the generation of ROS in macrophages induced by lipopolysaccharide (LPS). Additionally, it prevents the formation of ROS in rat bladder tissues induced by protamine sulfate and potassium chloride, while also prolonging the intervals between bladder contractions (Huang et al., 2014).
Quercetin exhibits significant antioxidant properties (Carrillo-Martinez et al., 2024). Research on epididymal semen in domestic dogs indicates that the addition of quercetin can effectively reduce ROS production during the cryopreservation of epididymal sperm (Gonzalez-Perez et al., 2025). Furthermore, another study demonstrates that quercetin enhances the activity of antioxidant enzymes in the liver tissue of rats suffering from cadmium-induced liver injury, reduces MDA content, alleviates cadmium-induced oxidative stress, and exerts notable antioxidant effects (Jiang et al., 2025). Additionally, electron spin resonance (ESR) experiments have confirmed that quercetin possesses the capability to scavenge oxygen free radicals (Ren et al., 2025).
Safflower polysaccharide (SPS) exhibits significant antioxidant effects (Liu et al., 2025). A study on freeze-thawed boar sperm demonstrated that SPS enhances the total antioxidant capacity of sperm by regulating superoxide dismutase activity, inhibiting lipid peroxidation, and scavenging free radicals, thereby improving the quality of freeze-thawed boar sperm (Li et al., 2025). Additionally, another study indicated that SP can modulate the expression of antioxidant enzymes and reduce free radical content in the liver tissues of mice with high-fat diet-induced metabolic associated fatty liver disease (MAFLD). Furthermore, in vitro experiments have shown that SPS can effectively scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) in hydrogen peroxide (H₂O₂)-stimulated hepatocytes (HepG2 cells) (Demirci and Yildiz Zeyrek, 2022).
3.2.3 Cardiovascular protective effect
Animal studies have demonstrated that HSYA can alleviate myocardial ischemia-reperfusion injury in rats by inhibiting the Toll-like receptor 4 (TLR4) signaling pathway. Furthermore, HSYA has been shown to improve hemodynamics and vascular abnormalities in a rat model of renovascular hypertension, effectively reducing blood pressure and hindlimb vascular resistance while increasing hindlimb blood flow. Additionally, HSYA mitigates the increase in aortic wall thickness, the expansion of cross-sectional area, and collagen deposition, while also inhibiting the activation of the renin-angiotensin system (RAS) and oxidative stress within the vascular system (Han et al., 2016). Research on a rat model of atherosclerosis-related ischemic stroke (ISFA) has revealed that HSYA can reduce carotid intima-media thickness, decrease arterial plaque and lipid deposition, regulate blood lipids, and downregulate the expression of inflammation-related genes (PRKCA, IKBKB), thereby exerting cardiovascular protective effects (Han et al., 2023). Furthermore, network pharmacology combined with in vitro cellular studies has confirmed that HSYA can reduce the activity of lactate dehydrogenase (LDH) and creatine kinase (CK) in H₂O₂-induced H9c2 cardiomyoblasts, promote the expression and nuclear translocation of Nrf2, decrease the generation of reactive oxygen species (ROS), while upregulating the mRNA expression of protein kinase B (Akt) and B-cell lymphoma-2 (Bcl-2) and downregulating the mRNA expression of caspase-3, thereby providing cardiovascular protective effects against myocardial ischemia (Zhang et al., 2023). Additionally, HSYA has demonstrated potential ameliorative effects on vascular inflammation-related diseases. Studies conducted on atherosclerosis (AS) models in rats and in vitro cell cultures have shown that HSYA can reduce lipid deposition, significantly alleviating the pathological changes associated with atherosclerosis. This suggests the potential application value of HSYA in the intervention of atherosclerosis (Zhang et al., 2025).
An in vitro study indicated that kaempferol can enhance lipid metabolism, reduce the formation of atherosclerotic plaques, and improve plaque stability through bidirectional targeted regulation of the p53-p21-p16 cell senescence pathway and activation of the Nrf2/HO-1/NQO1 antioxidant pathway, positioning it as a potential natural therapeutic candidate for cardiovascular diseases (Cai et al., 2025). Furthermore, another study demonstrated that kaempferol inhibits the tyrosine phosphorylation of the platelet-derived growth factor β receptor (PDGF-βR) and its downstream signaling pathways in rat aortic vascular smooth muscle cells (VSMCs), thereby suppressing VSMC proliferation. The abnormal proliferation of VSMCs is a core mechanism underlying atherosclerosis and vascular remodeling. This confirms that kaempferol exerts cardiovascular protective effects by regulating vascular cell proliferation (Kim et al., 2005).
In recent years, a novel flavonol glycoside isolated from safflower petals, along with several co-isolated known flavonoids and quinone chalcones, has demonstrated protective effects against hydrogen peroxide (H2O2)-induced apoptosis in H9c2 cardiomyocytes (Xie et al., 2016).
3.2.4 Antitumor activity
The role and mechanism of HSYAin anti-tumor activity have been extensively studied (Wang et al., 2024). In the H22 tumor-bearing mouse model, HSYA inhibits angiogenesis in hepatocellular carcinoma (HCC) by blocking the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways (Yang et al., 2015). A study utilizing the T-cell acute lymphoblastic leukemia (T-ALL) model Jurkat cells demonstrated that HSYA can inhibit the proliferation of Jurkat cells in a time- and dose-dependent manner, induce G0/G1 phase cell cycle arrest in a concentration-dependent manner, and downregulate the mRNA and protein expression of Notch1, c-Myc, and Hes1 (P < 0.001). This indicates that HSYA exerts anti-T-ALL effects by targeting the Notch1 signaling pathway, providing a new potential direction for drug research in the treatment of T-ALL (Hao et al., 2025). Furthermore, an in vitro study revealed that HSYA inhibits the proliferation, migration, and invasion of colorectal cancer cells (HCT116) through the PPARγ/PTEN/Akt signaling pathway, while exhibiting no toxicity to normal intestinal epithelial cells (Su and Lv, 2021). These findings suggest that HSYA possesses promising antitumor activity.
SPS exhibits significant inhibitory effects on the proliferation, metastasis, and invasion of tumor cells. In vitro studies have shown that SPS can markedly inhibit the proliferation of MCF-7 breast tumor cells in a dose-dependent and time-dependent manner. After a 72-hour intervention, the half maximal inhibitory concentration (IC50) of SPS on MCF-7 cells is determined to be 0.12 mg/mL (Health Department of Xinjiang Uygur Autonomous Region, 1985). Furthermore, SPS downregulates the expression of Bcl-2 protein while upregulating the expression of Bax protein, thereby promoting apoptosis in MCF-7 cells. It also reduces the expression of matrix metalloproteinase-9 (MMP-9) and increases the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), which inhibits the migration of tumor cells (Health Department of Xinjiang Uygur Autonomous Region, 1985). A study utilizing pancreatic cancer cell lines and patient-derived xenograft (PDX) models revealed that the polysaccharide HH1-1, derived from safflower, can inhibit pancreatic cancer cell proliferation, arrest the cell cycle at the S phase, induce apoptosis, and suppress tumor migration and invasion by binding to Galectin-3 and blocking the Galectin-3/EGFR/AKT/FOXO3 signaling pathway. Moreover, HH1-1 exhibits low toxicity, making it a potential candidate for pancreatic cancer treatment and providing experimental evidence for Galectin-3 targeted therapy (Yao et al., 2019).
3.2.5 Regulate lipid metabolism
In recent years, the medicinal value of safflower seeds has garnered considerable attention. Research indicates that safflower seed oil is abundant in various unsaturated fatty acids and demonstrates significant regulatory effects on lipid metabolism (Carta et al., 2021). Studies utilizing high-fat diet-induced obese mouse models have shown that supplementation with safflower oil effectively alleviates obesity-related symptoms, including increased body weight, liver weight, and epididymal fat weight, while concurrently reducing serum triglyceride and leptin levels (Thomas et al., 2020). By blending safflower oil with flaxseed oil, which is rich in ω-3 fatty acids, the ω-6/ω-3 fatty acid ratio of safflower oil can be optimized, thereby enhancing its health benefits (Arshad et al., 2025).
3.2.6Microbiota Modulating Effect
The regulation of gut microbiota represents a burgeoning area of research concerning safflower. A study that supplemented a high-fat and high-sugar diet in C57BL/6J mice with safflower seed oil revealed significant alterations in the cecal and colonic microbiota compared to the control group, characterized by reduced stability and notable changes at both the phylum and genus levels. These findings suggest that safflower seed oil may play a pivotal role in microbiota regulation. This research elucidates the connection between safflower, gut microbiota, and metabolic diseases, thereby laying the groundwork for the development of safflower-based therapeutic strategies for metabolic disorders (Danneskiold-Samsoe et al., 2017).
Fig.5.Fig6.These two images illustrate the various bioactive components of Carthamus tinctorius L. (safflower) and its mechanisms of action in anti-inflammation, antioxidant, cardiovascular protection, antitumor, lipid metabolism regulation, and intestinal flora regulation.
- Safety
Safflower is widely recognized as a common dietary supplement (HDS) associated with hepatotoxicity; however, establishing a direct causal relationship between hepatotoxicity and safflower is challenging. This difficulty arises from patients frequently using multi-component HDS in clinical practice, incomplete ingredient disclosure, and the potential presence of unlabeled additives. These factors pose practical challenges for the safety assessment and regulation of safflower-based HDS (Santos et al., 2021). Conversely, multiple studies have investigated the safety and toxicity profiles of safflower in humans. A Phase I clinical trial evaluating the safety and tolerability of HSYA revealed that all adverse reactions observed in healthy volunteers during the drug administration were mild and did not necessitate special treatment, with no significant differences compared to the control group. Moreover, no adverse events were reported after the discontinuation of the drug, indicating that HSYA possesses a favorable safety profile (Li et al., 2015).
SPS possess proven efficacy, low toxicity, and a favorable safety profile, indicating their broad application prospects in food science, medicine, and cosmetics. However, it is important to note that certain polysaccharides may exhibit cytotoxicity to normal cells at high concentrations or under specific conditions, necessitating further investigation to delineate their safe application boundaries (Bozbas et al., 2024).
- Pharmacokinetics
Pharmacokinetic studies conducted on healthy Chinese volunteers have demonstrated that intravenously administered HSYA exhibits rapid absorption and elimination, with no significant accumulation observed. Within the dose range of 25-75 mg, both the area under the plasma concentration-time curve (AUC (0-t) and AUC (0-∞)) and the peak plasma concentration (C(max)) of HSYA show a strong linear relationship with the administered dose. Following continuous administration of 50 mg of pure HSYA injection powder (IPPH) for 7 days, both the peak plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC (0-∞)) were significantly reduced, while the half-life (t(1/2)) was notably prolonged. Furthermore, the study revealed gender differences in the pharmacokinetics of HSYA, with male volunteers exhibiting generally lower peak plasma concentrations (C(max)) and AUC values compared to female volunteers (Li et al., 2015). This suggests that gender may influence the therapeutic efficacy of the drug by affecting the pharmacokinetic characteristics of HSYA in the body.
6.Challenges, Opportunities, and Development Prospects in Safflower Research
The research field related to safflower still harbors numerous unknowns awaiting exploration. Plant breeding and the study of stress resistance mechanisms represent one of the highly promising directions. For instance, recent studies have found that the combined application of salicylic acid and sodium nitroprusside can alleviate the development of safflower seedlings under zinc toxicity conditions, yet the underlying mechanisms remain unclear (Namdjoyan et al., 2017). A deeper understanding of these interactions can help unveil the mechanisms by which safflower copes with stress, providing new strategies for developing safflower varieties with high stress resistance and pharmacological activity. In addition, the integrated application of omics technologies (including genomics, transcriptomics, metabolomics, and proteomics) is expected to provide significant technical support for a comprehensive understanding of the biological characteristics of safflower (Lu et al., 2025; Peng et al., 2025; Qin et al., 2025; Shen et al., 2025; Wu et al., 2025; Zhang et al., 2025), thereby offering biological basis for the cultivation of safflower varieties with enhanced pharmacological activity (Ren et al., 2025).
In pharmacology, although various active components have been identified from safflower, further research is necessary to fully understand the pharmacological properties of these components, particularly their interactions with other drugs, such as whether safflower influences the efficacy of other medications. This understanding is crucial for elucidating the pharmacological mechanisms of safflower and for developing safer and more effective safflower-based therapeutic drugs (Korkmaz, 2024). Notably, the research team also discovered that structural factors, including molecular weight, differences in monosaccharide composition, and branching degree, significantly influence the biological activities of safflower, such as immunomodulation, antioxidant properties, and antitumor effects (Bozbas et al., 2024). These findings present potential directions for future research.
The research achievements regarding safflower and its active constituents have not only enriched the understanding of its chemical essence and biological functions but have also provided critical theoretical support for its applications in ethnopharmacology (including modern interpretations of traditional efficacy), the development of functional foods, and the research and development of new drugs. These findings have also illuminated pathways for further exploration of its mechanisms of action and the optimization of clinical application protocols (Wang et al., 2025). The practice of combining safflower with other natural products or synthetic compounds has provided new insights into the multi-component treatment of diseases. The Qingre Bawei Capsule, a representative Mongolian medicinal formula composed of safflower and seven other medicinal ingredients, demonstrates remarkable efficacy in clearing heat and detoxifying, and is employed in the treatment of inflammatory diseases such as COVID-19 (Ji et al., 2020). The Danhong Injection (DHI), formulated from extracts of safflower and Salvia miltiorrhiza, is widely utilized as an adjunctive therapy for cardiovascular diseases, exhibiting significant therapeutic effects without inducing additional adverse reactions (Kan et al., 2025). With ongoing advancements in the study of the pharmacological mechanisms of safflower, safflower-based compounds are anticipated to be further developed, providing new therapeutic strategies for a range of diseases, including inflammatory diseases and tumor-related conditions.
In summary, the phytochemical and pharmacological effects of safflower have attracted significant attention. Researchers have isolated various extracts and active compounds (Wang et al., 2025) and discovered numerous biological activities. However, additional research is required to explore the pharmacological activities of safflower, particularly its role in microbiota regulation. Future studies should prioritize clarifying cultivation conditions, elucidating the mechanisms underlying various pharmacological effects, and identifying potential contraindications for interactions with other foods and drugs.
Abbreviation
| Abbreviation | English Full Name |
| HSYA | hydroxysafflor yellow A |
| LPS | lipopolysaccharide |
| IL-1β | interleukin-1β |
| IL-6 | interleukin-6 |
| TNF-α | tumor necrosis factor-α |
| LCN2 | lipocalin-2 |
| JAK2/STAT3 | janus kinase 2/signal transducer and activator of transcription 3 |
| YAP/JNK | yes-associated protein/c-jun n-terminal kinase |
| TACE | TNF-α converting enzyme |
| TNFR1 | tumor necrosis factor receptor 1 |
| NF-κB | nuclear factor-κB |
| ICAM-1 | intercellular adhesion molecule-1 |
| DSS | dextran sulfate sodium |
| SOD | superoxide dismutase |
| GPx | glutathione peroxidase |
| ROS | reactive oxygen species |
| MDA | malondialdehyde |
| CIRI | cerebral ischemia-reperfusion injury |
| OXPHOS | oxidative phosphorylation |
| ALS | amyotrophic lateral sclerosis |
| ESR | electron spin resonance |
| DPPH | 1,1-diphenyl-2-picrylhydrazyl |
| TLR4 | toll-like receptor 4 |
| RAS | renin-angiotensin system |
| ISFA | ischemic stroke following atherosclerosis |
| LDH | lactate dehydrogenase |
| CK | creatine kinase |
| Nrf2 | nuclear factor erythroid 2-related factor 2 |
| Akt | protein kinase B |
| Bcl-2 | B-Cell lymphoma-2 |
| PDGF-βR | platelet-derived growth factor β receptor |
| VSMCs | vascular smooth muscle cells |
| HCC | hepatocellular carcinoma |
| ERK/MAPK | extracellular signal-regulated kinase/mitogen-activated protein kinase |
| T-ALL | t-cell acute lymphoblastic leukemia |
| PPARγ | peroxisome proliferator-activated receptor γ |
| PTEN | phosphatase and tensin homolog |
| SPS | safflower polysaccharide |
| IC50 | half Maximal inhibitory concentration |
| MMP-9 | matrix metalloproteinase-9 |
| TIMP-1 | tissue inhibitor of metalloproteinases-1 |
| PDX | patient-derived xenograft |
| MAFLD | metabolic associated fatty liver disease |
| HDS | dietary supplement |
| AUC | area under the plasma concentration-time curve |
| C(max) | peak plasma concentration |
| t(1/2) | half-life |
| SSR | simple sequence repeat |
| PIC | polymorphism information content |
| InDel | insertion-deletion |
| SRAP | sequence-related amplified polymorphism |
| SCoT | start codon targeted polymorphism |
| POGP | peroxidase gene polymorphism |
| DArTseq | diversity arrays technology sequencing |
| rhFGF10 | recombinant human fibroblast growth factor 10 |
| MSPD | matrix solid-phase dispersion |
| HPLC-DAD | high-performance liquid chromatography-diode array detection |
| UPLC-Q-TOF-MS | ultra-performance-liquid-chromatography-quadrupole-time-of-flight-mass -spectrometry |
| HSCCC | high-speed counter-current chromatography |
| 1H NMR | hydrogen nuclear magnetic resonance |
| 13C NMR | carbon nuclear magnetic resonance |
| NF | n-feruloylserotonin |
| NP | n-(p-coumaroyl)serotonin |
| SCE | safflower seed coat extract |
| PAHA | phenylpropanoid amides of 5-hydroxytryptamine |
| IPPH | pure HSYA injection powder |
Competing interests
The authors declare no competing interests.
Funding
This research was supported by the following funding sources: the National Natural Science Foundation of China (82474264, 82205044, 82174170), Shenzhen Municipal Government (2022QD056), Taiji Group Co., Ltd. for the development of the Shenqi Yiqi formula, support from the Institutes of Integrative Medicine, Fudan University, the Karamay Key R&D Program (2025BA0108), the Youth Fund of the Xinjiang Uygur Autonomous Region Natural Science Foundation (Project No. 2025D01B23), the Tianchi Scholar Program at Xinjiang Medical University (Talent Program), and the Xinjiang Hetian Traditional Chinese Medicine Research Key Laboratory. Additionally, Huashan Hospital supported the basic research on the intervention of several airway inflammatory diseases by the Shenqi Yiqi formula (2022QD056) and the medical research plan for the prevention of common diseases in employees participating in the China Railway First Group plateau project (HIM-2024-0081). Fudan University also provided support for the following projects: the technical service contract for the China Railway First Group Plateau Area Medical Guarantee and Disease Prevention Informatization Project, the multi-center, double-blind, randomized, controlled clinical studies of Qingre Bamei capsules for treating acute exacerbation of COPD (Phlegm-Heat Lung Syndrome), the multi-center, double-blind, randomized, controlled clinical studies of Qingre Bamei capsules for treating acute exacerbation of bronchiectasis (Phlegm-Heat Lung Syndrome), and the secondary development research of the Bushen Fangchuan tablets.
Authors’ Contributions
Jiangyue Liu collected and analyzed the literature, drafted the manuscript, and prepared the figures and tables.
Maimaititusun Yalikun contributed to the study conception and design, revised the manuscript critically for important intellectual content, and supervised the overall progress of the work.
Wenjing Chen participated in data organization, manuscript revision, and provided constructive suggestions for improving the structure and content.
Jingcheng Dong conceived and supervised the project, provided financial and academic support, critically reviewed the final manuscript, and approved the version to be submitted for publication.
All authors have read and approved the final manuscript.
Main Corresponding Author Information
Jingcheng Dong is the main corresponding author of this work. He is a Chair Professor and doctoral advisor at Fudan University, Head of the National “Double First Class” Discipline of Integrative Medicine, Director of the Institutes of Integrative Medicine at Fudan University, and Chief of the Department of Integrative Medicine at Huashan Hospital. His research primarily focuses on integrative medicine in pulmonary diseases, oncology, geriatric disorders, and the pharmacological and modern research of traditional medicine. He has published more than 440 peer-reviewed papers and has received six provincial-level scientific awards.
Acknowledgements
The authors gratefully acknowledge the support and assistance provided by the SCO National Multifunctional Center in the collection of traditional Chinese medicinal resources.
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