The TCMSP platform (http://old.tcmsp-e.com/tcmsp.php) was utilized to search for chemical constituents in hawthorn leaves. The screening criteria of oral bioavailability ≥15% and drug-likeness ≥0.18 were applied to obtain the active ingredients and their targets. Additionally, information from literature and the SwissTargetPrediction database (http://swisstargetprediction.ch/) was incorporated to further supplement the active ingredients of hawthorn and the corresponding gene targets (Basavarajappa et al., 2023). The collected data was visually analyzed using Cytoscape 3.9.1 software, and the connectivity centrality was calculated with the assistance of the CytoNCA plug-in. To determine the key targets of hawthorn in cancer treatment, a screening condition of connectivity centrality >2 times the median value was applied. The target data was further analyzed for metabolic pathways using the David platform (https://david.ncifcrf.gov/home.jsp) (Yang J. et al., 2023). Data visualization was performed using the Chiplot platform (https://www.chiplot.online/).

Utilizing the TCMSP database and integrating various literature, we screened 19 active ingredients of hawthorn and pinpointed 67 core targets linked to these compounds. The pathways enriched by these core targets are closely associated with cancer. This suggests that hawthorn may possess a notable anticancer effect, with the identified active ingredients possibly being the main components of hawthorn responsible for exerting anticancer efficacy. Figure 2 visually presents the relationship network among drug, active ingredients, and targets, along with a Sankey diagram illustrating the correlation between targets and pathways.

The most abundant chemical ingredient in hawthorn is a class of flavonoids and their glycosides, with apigenin and luteolin as aglycones (Rayyan et al., 2005; Zhang J. et al., 2022). Apigenin-based glycosides include vitexin and isovitexin, while luteolin-based glycosides include orientin and isoorientin. Hawthorn also contains flavonols and their glycosides, such as quercetin, kaempferol, rutin, hyperin, and isorhamnetin (Zhang et al., 2010; Jurikova et al., 2012).

In recent years, multiple studies have demonstrated that flavonoids rich in hawthorn play an anticancer role through various signal transduction pathways. For instance, vitexin has been discovered to impede the growth, blood vessel formation, and stemness of endometrial cancer cells. It achieves this by targeting the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway (Liang C. et al., 2023). The mechanism of orientin involves the regulation of protein kinase C alpha (PKCα)/extracellular protein-regulated kinases (ERK)/activator protein-1 (AP-1)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Upon exposure to orientin, the activation of PKCα is suppressed, subsequently impacting the aforementioned cellular signal transduction pathways and ultimately impeding the invasion of breast cancer cells (Kim et al., 2018). Isoorientin induced programmed cell death by activating the reactive oxygen species (ROS)-mediated mitogen-activated protein kinase (MAPK)/STAT3/nuclear factor kappa B (NF-κB) pathway. Moreover, it regulated cellular migration by modulating the Akt/glycogen synthase kinase 3β (GSK-3β)/β-catenin pathway (Zhang T. et al., 2022). Hyperoside has demonstrated its efficacy in inhibiting the hypoxia-induced proliferation of cancer cells by enhancing ferrous accumulation in the adenosine monophosphate-activated protein kinase (AMPK)/heme oxygenase-1 (HO-1) axis (Chen et al., 2020). Isorhamnetin primarily acts through the peroxisome proliferator-activated receptor γ (PPARγ)/phosphatase and tensin homolog (PTEN)/Akt pathway. It suppresses cell proliferation and the transition from the G0/G1 phase to the S phase in bladder cancer by suppressing the expression of carbonic anhydrase IX (CA9), thereby diminishing tumor formation (Zhang P. et al., 2023).

These compounds are also widely distributed in hawthorn, and the basic units are (+)-catechin, (−)-epicatechin, and leucocyanidin. They can polymerize with each other to form dimers like procyanidin B2, B4, and B5, as well as trimers like procyanidin C1 (Jurikova et al., 2012).

Epidemiological studies have demonstrated that (−)-epicatechin and proanthocyanidins exhibit strong resistance against various types of cancer and can produce therapeutic effects through different mechanisms. Research conducted on mice has unveiled that (−)-epicatechin inhibits the proliferation, migration, and invasion of breast cancer cells, resulting in reduced tumor size and ultimately enhancing the survival rate of cancer-afflicted mice (Pérez-Durán et al., 2023). Furthermore, antiproliferative and apoptotic effects have been demonstrated by procyanidin B2, which induces autophagy by regulating the Akt/mechanistic target of the rapamycin (mTOR) signaling pathway (Li Y. et al., 2021). Procyanidin C1 exhibits anticancer properties by inducing DNA damage, arresting the cell cycle, and augmenting the expression of checkpoint kinases (Koteswari et al., 2020).

The pentacyclic triterpenoids represented by maslinic acid, corosolic acid, oleanolic acid, and ursolic acid are the primary triterpenoids found in hawthorn (López-Hortas et al., 2018; Zhang J. et al., 2022). Among them, ursolic acid has the highest concentration. Research conducted by (Liao et al., 2022) reveals that the progression of cancer heavily relies on the stemness and metastasis of cancer cells. Ursolic acid effectively obstructs the stemness of cancer cells by significantly reducing the expression of stemness biomarkers. Besides, it modifies the migration and invasion abilities of the cancer cells by regulating the MAPK-ERK/vascular endothelial growth factor (VEGF)/matrix metalloproteinase-9 (MMP-9) signaling pathway, and polyamine metabolism (Zong et al., 2022).

Lately, researchers have shown increased interest in the potential anticancer properties of corosolic acid. Studies have demonstrated that corosolic acid possesses the ability to diminish the level of cyclin-dependent kinase 19 (CDK19)-mediated O-GlcNAcylation within liver cancer cells, thereby impeding the advancement of cancer (Zhang C. et al., 2021). Additionally, corosolic acid has been observed to reduce invasion and chemoresistance in cancer cells by inducing oxidative stress in mitochondria and liposomes (Jin et al., 2021).

Maslinic acid frequently appears alongside its isomeric counterpart, corosolic acid. It exhibits remarkable inhibitory properties against cancer cells and achieves this by inducing apoptosis through the regulation of the AMPK/mTOR signaling pathway (Wei et al., 2019). Furthermore, experimental analyses conducted in vitro have shown that maslinic acid can exert toxic effects on cancer cells by upregulating the expression of DNA damage and repair-related proteins (Lu et al., 2020).

The content of organic acids in hawthorn’s active ingredients is second only to flavonoids, and they play a vital role in the prevention and treatment of cancer. Among these organic acids, chlorogenic acid stands out for its notable anticancer properties. It possesses the capability to hinder the epithelial-mesenchymal transition (EMT) of cancer cells, lessen their fluidity and invasiveness, and impede their growth (Xue W. et al., 2023). Additionally, chlorogenic acid effectively suppresses the nuclear transcription of NF-κB p65 by disrupting the NF-κB/EMT signaling pathway. This contributes to the prevention of cancer cell metastasis and fosters anticancer immunity (Zeng et al., 2021).

β-sitosterol and stigmasterol are two steroidal compounds discovered in hawthorn. Recent research has shown that β-sitosterol possesses the capability to hinder the progression and infiltration of colorectal cancer cells by impeding the wingless/integrated (Wnt)/β-catenin pathway (Gu et al., 2023). Stigmasterol has been observed to activate protective autophagy in gastric cancer cells through the inhibition of the Akt/mTOR pathway (Zhao et al., 2021).

The formidable capacity for proliferation displayed by cancer cells is among the primary factors contributing to their resistance to effective elimination. This ceaseless proliferation additionally imposes a substantial burden on the body. Therefore, the inhibition of cancer cell proliferation has arisen as a pivotal strategy in the treatment of cancer. In contemporary scientific research, the utilization of separation and purification technology is commonly employed to investigate novel compound information found in distinct medicinal sections of hawthorn. To validate its efficacy in combating cancer, experiments assessing cytotoxicity are commonly conducted (Hsiao and Liu, 2010; Zimmermann-Klemd et al., 2022).

Building on this concept, neolignans with antioxidant activity have been successfully isolated from hawthorn seeds (Huang et al., 2013a; Li L. Z. et al., 2013; Huang et al., 2013b), demonstrating significant inhibition of cancer cell growth in a dose-dependent manner. Research on the medicinal potential of hawthorn leaves revealed that methanol, acetone (Mohammedsaeed and Mohamad, 2023), and ethyl acetate extracts (Mustapha et al., 2015) exhibit notable anti-proliferative effects on cancer cells. Triterpenoids (Min et al., 2000) and total flavonoids (Tang et al., 2010; Diao et al., 2019) isolated from these extracts also showed promise in inhibiting cancer cell activity. Hawthorn buds extract displayed significant cytotoxicity in four human cancer cell lines (Rodrigues et al., 2012), while the petroleum ether extract of hawthorn stems exhibited stronger inhibition of cancer cell proliferation and promotion of apoptosis compared to water and ethanol extracts (Maldonado-Cubas et al., 2020). Triterpenoids (Ahn et al., 1998; Qiao et al., 2015), neolignans (Guo et al., 2019a; Shang et al., 2020), polyphenols (Żurek et al., 2021), total flavonoids (Zhang et al., 2004), and aromatic compounds (Guo et al., 2018; Zhao et al., 2019) found in hawthorn fruit showed potent anticancer cell proliferation and antioxidant activity. Notably, polyphenol components in hot water extract of dried hawthorn fruit were found to significantly inhibit tumor formation and reduce tumor incidence (Kao et al., 2007). In addition, the polyphenolic components in hawthorn whole plant extract have demonstrated a reduction in cell viability and reactive oxygen species formation in a dose- and time-dependent manner, indicating both cytotoxic and antioxidant properties (Belščak-Cvitanović et al., 2014). Simultaneously, hawthorn extract has a certain anti-mutation effect while causing tumor cell death (Zhu, 2012) and inhibiting its proliferation (Sun et al., 2013; Mustapha et al., 2016a).

The bioactive ingredients abundant in hawthorn have been identified as the basis for its anticancer properties. Through basic experimentation, preliminary confirmation of the intervention impact and mechanism of these chemical ingredients on cancer has been achieved. Vitexin, the primary active ingredient in hawthorn leaves, possesses the capability to influence the expression of specific genes in the signaling pathway associated with “anti-proliferation,” rendering it a potential drug for breast cancer treatment and prevention through the mediation of miRNA (Najafipour et al., 2022). Hyperoside is also highly acclaimed in the realm of cancer therapy (Peng et al., 2023), as it has been demonstrated to effectively impede the growth of cervical cancer cells by targeting the V-Myc myelocytomatosis viral oncogene homolog (C-MYC) gene (Guo W. et al., 2019). Additionally, it has exhibited promise in managing non-small cell lung cancer (NSCLC) with the T790M mutation. By upregulating the expression of forkhead box protein O1 (FoxO1), it hinders cancer cell proliferation and induces apoptosis (Hu et al., 2020). Stigmasterol, renowned for its potent biological activity, has emerged as a notable area of interest in the exploration of natural active ingredients present in hawthorn. Recent investigations have unveiled that retinoic acid-related orphan receptor C (RORC) can specifically target stigmasterol, leading to the suppression of lung cancer cell proliferation. This discovery provides a promising direction for the development of potential therapeutic strategies to combat lung cancer (Dong et al., 2021).

Apoptosis, also known as programmed cell death, is a crucial mechanism that regulates and examines cells by employing caspase proteolytic enzymes under specific physiological or pathological circumstances. This process efficiently eliminates non-functioning, abnormal, harmful, and misplaced cells (Carneiro and El-Deiry, 2020). Apoptotic cells demonstrate noticeable changes in morphology, including shrinkage, chromatin condensation, and the formation of apoptotic bodies (Wong, 2011). There are two primary signaling pathways responsible for inducing cell apoptosis: the extrinsic/death receptor pathway and the intrinsic/mitochondrial pathway (Ghobrial et al., 2005; Wong, 2011; Carneiro and El-Deiry, 2020).

For a long time, apoptosis has been recognized as a crucial mechanism in preventing tumor development, and many cancer treatments rely on promoting effective apoptosis (Singh and Lim, 2022). In recent years, researchers have focused on discovering cancer treatment methods that target apoptosis-related molecules to improve treatment sensitivity and specificity. When the body contains elevated levels of anti-apoptotic proteins such as B cell lymphoma-2 (Bcl-2) and decreased levels of pro-apoptotic proteins like Bcl2-associated X protein (BAX), cancer cells exhibit anti-apoptotic activity, and malignancy increases. Hence, the utilization of the pro-apoptotic effects exhibited by members of the Bcl-2 protein family has emerged as a crucial approach in the treatment of cancer (Kaloni et al., 2023). In the investigation of the anticancer properties of hawthorn’s active ingredients, the researchers discovered that chlorogenic acid (Wang et al., 2019) and hyperoside (Qiu et al., 2019) can modify the Bax/Bcl-2 ratio, resulting in a significant induction of apoptosis and displaying their therapeutic potential in cancer treatment.

Moreover, in cancer cells, the protein caspase plays a pivotal role in both triggering and executing apoptosis. The hindered activity or impaired function of caspase expedites the progression of cancer. Activating caspase activity has long been acknowledged as a significant indication of cell apoptosis and has emerged as a noteworthy strategy in the clinical treatment of cancer. Recent research has revealed that hawthorn extract and its active ingredients possess the potential to activate caspase and stimulate apoptosis. Specifically, hawthorn peel polyphenol extract and pulp polyphenol extract have been shown to induce apoptosis in breast cancer cells, operating through the mitochondrial pathway. This is evident from the increased expression of caspase-3 and caspase-9 (Li T. et al., 2013). Additionally, Hawthorn oligomeric procyanidin extracts have demonstrated the ability to enhance apoptosis and exhibit an anticancer effect by modulating the expression levels of caspase-9 in the mitochondrial pathway, caspase-8 in the death receptor pathway, and caspase-3, serving as a common downstream regulator of both pathways. This discovery offers a fresh approach for treating colon cancer patients in clinical practice (Sun et al., 2022). Hawthorn leaf extract showed the ability to enhance the apoptosis of cancer cells (Omairi et al., 2020). This effect primarily involves the exogenous apoptosis pathway and triggers caspase-8 cleavage (Mustapha et al., 2016b). Furthermore, in experiments where the ethanol extract of hawthorn was applied to liver cancer cell lines, it was observed that as the concentration of the extract increased and the duration of exposure lengthened, there was a notable suppression of cell proliferation and an increase in apoptosis. These outcomes were linked to the activation of the caspase pathway and a significant rise in the levels of intracellular cleaved-caspase3 and Bax/Bcl-2 proteins (Peng et al., 2016).

The role of the endoplasmic reticulum pathway in apoptosis is also crucial (Wong, 2011). In normal physiological conditions, amino acids are dehydrated and condensed to form peptide chains, which then enter the endoplasmic reticulum for processing and protein formation. Correctly folded proteins are secreted out of the cell by the Golgi apparatus, and protein synthesis and decomposition maintain a dynamic balance. However, specific circumstances such as elevated cellular Ca²⁺ levels, changes in redox status, decreased ATP levels, increased misfolded proteins, and excessive protein buildup can disrupt this equilibrium, leading to endoplasmic reticulum stress (Jin and Sun, 2020). Excessive stress response triggers intracellular apoptosis signals, promoting cell apoptosis. In a research study carried out by Ye et al. (2022), it was observed that isorhamnetin, an anticancer active ingredient found in hawthorn, can induce endoplasmic reticulum stress-related reactions. This is achieved by activating both the endogenous mitochondrial apoptosis pathway and the exogenous death receptor pathway, consequently provoking apoptosis in breast cancer cells. Tang et al. (2023) combined transcriptomic data with experimental results and discovered that corosolic acid can instigate endoplasmic reticulum stress by activating the mitochondrial pathway of apoptosis, leading to significant apoptosis in cell lines. These discoveries offer valuable insights into potential therapeutic approaches for cancer treatment.

The regulation of cell growth, development, and differentiation is critically dependent on the cell cycle, which is highly organized and strictly controlled by a unique system to ensure the precise replication of genetic materials and cell division (Otto and Sicinski, 2017). The normal cell cycle comprises interphase, which includes the G1, S, and G2 phases, followed by the mitosis phase (M phase). The transition from one stage to the next is known as the cell cycle checkpoint (Matthews et al., 2022). In cancer cells, various cumulative mutations lead to abnormal mitotic signals, further leading to unplanned proliferation and increased chromosome number uncertainty (Malumbres and Barbacid, 2009). Cell cycle arrest enables the detection and repair of cell damage, reduces the occurrence of mutations, and ensures genome stability, thereby preventing the onset and progression of cancer. Therefore, the regulation of the cell cycle is of great significance in cancer treatment and prevention.

In recent years, as numerous scholars have made significant progress in investigating the anticancer mechanisms of hawthorn, the participation of hawthorn extract and its primary active ingredients in cell cycle regulation has been identified. The two key proteins involved in this process are cyclins and cyclin-dependent kinases (CDKs) (Matthews et al., 2022). Wen et al. (2017) specifically extracted triterpenoid-rich fraction S9 and ursolic acid from hawthorn fruit. They observed a decrease in the levels of Cyclin-D1 and CDK4 proteins when these ingredients were used to treat cells. Furthermore, the expression of p21^WAF1/CIP1, a crucial member of the CDK inhibitor family, increased, resulting in significant cell G1 phase arrest. The homogeneous polysaccharide extracted from hawthorn can induce cell cycle arrest in S and G2/M phases by down-regulating Cyclin A1/D1/E1 and CDK-1/2 expression (Ma et al., 2020). Orientin, a compound commonly found in medicinal plant parts such as hawthorn, has shown promising anticancer properties. Research has demonstrated its ability to regulate cyclins and CDKs, effectively halting the cell cycle progression from the G0/G1 phase to the S phase (Thangaraj et al., 2019).

Autophagy is a catabolic process that is highly conserved in eukaryotes and plays a crucial role in maintaining cellular energy supply, material circulation, and the self-renewal of cells (Zhou et al., 2022). Its role in cancer development is complex and can be compared to a metaphorical “double-edged sword” (Debnath et al., 2023). In the early stages of cancer, autophagy activation contributes to normal cellular physiological metabolism and helps maintain the stability of the intracellular environment by limiting genomic damage and mutation, as well as selectively removing misfolded proteins. However, as cancer progresses to an advanced stage, autophagy is activated in the absence of nutrition and hypoxia. In this context, autophagy acts as a dynamic degradation and recycling system, breaking down macromolecules and providing nutrients for cancer cell growth (Li X. et al., 2020). Therefore, the appropriate activation and inhibition of autophagy is a potential direction for cancer treatment.

Flow cytometry analysis demonstrated that phenylpropanoid derivatives derived from hawthorn fruits activated protective autophagy in HepG2 cells and demonstrated anticancer activity (Guo et al., 2019b). In breast cancer, vitexin was found to notably enhance the expression of genes associated with autophagy, including autophagy-related 5 homolog (ATG5), Beclin-1, and microtubule-associated protein 1 light chain 3 II (LC3-II), thereby promoting autophagy and resulting in therapeutic benefits (Ghazy and Taghi, 2022).

Highly invasive cancer is characterized by the strong ability of cancer tissues to migrate to normal tissues. Cancer cells originate from the primary lesion and can invade the host’s blood and lymphatic vessels, spreading to distant parts of the body through blood vessels or body cavities. They can evade the host’s immune surveillance and reproduce, ultimately leading to new angiogenesis and metastasis (Xiong et al., 2022). During this process, the pathogenic body alters the adhesion and migration ability of cancer cells through factors such as ECM degradation, vascular factor production, EMT modulation, and TME regulation. Therefore, it is possible to inhibit cancer cell metastasis and delay the progression of cancer by targeting these mechanisms.

ROS, which are products of oxygen consumption or cell metabolism, have the ability to regulate the development and survival of cancer by influencing the tumor environment and tumor matrix ingredients (Cheung and Vousden, 2022). ROS at different concentrations play distinct roles in cancer cells. Low concentrations promote cancer occurrence, while high concentrations increase oxidative damage to cancer cells, potentially leading to their death through ROS-dependent death signals (Liang R. S. et al., 2023). According to current beliefs, the buildup of intracellular ROS has the potential to trigger different types of cancer cell death (Villalpando-Rodriguez and Gibson, 2021). As a result, controlling the level of intracellular ROS has emerged as a promising and effective strategy for treating cancer.

ROS is a well-known apoptosis-stimulating factor (Pant et al., 2017). Current studies have demonstrated that certain anticancer active ingredients found in hawthorn, such as isoorientin (Xu et al., 2020), isorhamnetin (Li Y. et al., 2022), and ursolic acid (Kang et al., 2022), can play a role through the ROS-mediated mitochondrial-dependent apoptosis pathway. It is mainly manifested in the induction of ROS production after drug treatment. The significant accumulation of ROS disrupts the integrity and function of mitochondria, ultimately activating caspase-3 or caspase-9 and initiating apoptosis (Tu et al., 2021). Additionally, ROS production triggers endoplasmic reticulum stress, which results in the accumulation of Ca²⁺ and the induction of apoptosis in cancer cells. Stigmasterol (Bae et al., 2020) and β-sitosterol (Bae et al., 2021) can enhance ROS production and endoplasmic reticulum stress through the endoplasmic reticulum-mitochondrial axis, thereby triggering pro-apoptotic signals and exerting anticancer effects.

Earlier research has established a significant link between inflammation and the creation of cancer cells, suggesting that specific inflammatory reactions may contribute to the development of cancer (Mantovani et al., 2008). Consequently, targeting molecules that inhibit inflammation and participate in inflammatory processes may be a good cancer prevention and treatment strategy. Recent research on orientin has demonstrated its ability to decrease cell viability, lower the expression of inflammatory cytokines, and suppress the production of inflammatory mediators, ultimately impeding the advancement of cancer (Tian et al., 2019).

The PI3K/Akt pathway is a well-known signaling pathway implicated in cancer (Murugan, 2019). An experiment has provided evidence that vitexin can promote apoptosis in A549 cells via the PI3K/Akt/mTOR pathway. This process coincides with a reduction in the expression levels of p-PI3K, p-Akt, and p-mTOR, implying that vitexin possesses therapeutic potential in NSCLC (Liu et al., 2019). Similarly, hyperoside has been discovered to induce cell cycle arrest in the G1 phase by inhibiting this pathway in studies involving hepatocellular carcinoma (Wei et al., 2021). Additionally, isorhamnetin has demonstrated its ability to induce apoptosis and impede gallbladder cancer cells cycle through this pathway, providing new avenues for cancer treatment (Zhai et al., 2021).

Cancer initiation, maintenance, and progression can be linked to abnormal Wnt signaling (Zhang and Wang, 2020). This signaling pathway encompasses two major parts: the classic Wnt/β-catenin pathway and the non-canonical Wnt pathway. The latter operates independently of β-catenin’s transcriptional activity (Semenov et al., 2007).

A study on the methanol extract of hawthorn berries revealed its potential for inhibiting breast cancer cell growth and arresting the cell cycle at the G1/S phase through the regulation of the Wnt signaling pathway (Kombiyil and Sivasithamparam, 2023). Furthermore, hawthorn polysaccharide extract may hinder the activation of the Wnt/β-catenin signaling pathway by upregulating miR-146a-5p levels, resulting in the suppression of AGS gastric cancer cell proliferation and induction of apoptosis (Li X. P. et al., 2021). Additionally, it has been discovered that ursolic acid can impede the malignant phenotype of colorectal cancer and interrupt the cell cycle by mitigating the Wnt/β-catenin signaling axis (Zhao et al., 2023).

This signaling pathway can regulate a variety of cellular mechanisms, thereby affecting biological processes. In the context of cancer, this pathway is particularly significant as it affects cancer proliferation, apoptosis, invasion, and metastasis (Peluso et al., 2019).

Scientific investigations have demonstrated that hawthorn acid, a notable constituent of hawthorn, possesses the capacity to alter the levels of ROS in malignant cells, ultimately resulting in programmed cell death (Jain and Grover, 2020). Moreover, it can repress the activity of proteins linked to the MAPK/ERK signaling pathway to hinder cell migration and invasion. These findings emphasize its potential as a promising drug for combating cancer (Liu et al., 2020). In a separate study on the effects of isorhamnetin on oral squamous cell carcinoma cells, it was discovered that isorhamnetin has the capability to halt the cell cycle during the G2/M phase and instigate apoptosis via ROS and ERK/MAPK pathways (Chen et al., 2021).

NF-κB is a crucial inducible transcription factor that plays a significant role in cell proliferation, differentiation, apoptosis, and carcinogenesis. Upon receiving internal and external stimuli, cells activate this signaling pathway, which results in the binding of nuclear factors to specific genes and the subsequent regulation of target gene expression (Chauhan et al., 2022; Deka and Li, 2023).

Frequently, the stimulation of this signaling cascade is accompanied by the emergence of cancer or inflammation (Taniguchi and Karin, 2018). In an investigation carried out by Tao J. Y. et al. (2023), it was elucidated that the activation of the NF-κB signaling pathway can be impeded by orientin and curb the proliferation and migration of cancer cells in vitro. Similarly, Wang L. et al. (2020) detected that chlorogenic acid can hinder the activation of this signaling pathway and the expression of downstream anti-apoptotic genes in cells, displaying a noteworthy inhibitory impact on the proliferation of lung adenocarcinoma cells.

The speedy transmission of signals from the cell membrane to the nucleus is facilitated by this pathway, which regulates the expression of downstream target genes through the activation of STAT and plays a crucial role in governing cancer cell proliferation and metastasis (Xue C. et al., 2023). STAT3, a key member of the STAT protein family, and its excessive activation contribute to the promotion of malignant biological behavior (Huynh et al., 2019; Zou et al., 2020).

By investigating the impact of vitexin on the STAT3 signaling pathway and key cancer markers, researchers have demonstrated that vitexin can successfully disrupt the sustained activation of JAK1, JAK2, and STAT3 in hepatocellular carcinoma (HCC) cells. These findings suggest that vitexin may serve as a potent inhibitor of the STAT3 pathway, offering the potential to suppress the proliferation and invasion of HCC cells (Lee et al., 2020).

p53, a well-researched suppressor of tumor growth, plays a crucial role in initiating various biological responses. Its abnormal activation has a strong connection to the onset and progression of cancer (Huang, 2021; Shen et al., 2023). Yang et al. (2013) observed an upregulation of p53 expression and its downstream genes, p21^WAF1 and Bax, upon exposure of oral cancer cells to vitexin. When p53 activity was suppressed, vitexin lost its anticancer effect, suggesting that vitexin can induce apoptosis through the p53-dependent pathway.