Based on the latest data from the International Agency for Research on Cancer (IARC), new cases of CRC accounted for 10.2% of all incident malignant neoplasms, making it the third most common cancer worldwide. CRC-associated death accounts for 9.3% of all malignant neoplasms, making it the second deadliest cancer after lung cancer (Bray et al., 2024; Global Nutrition Target Collaborators, 2025). Due to the influence of dietary habits, lifestyle and economic development (Vernia et al., 2021), CRC is becoming more prevalent among younger people. The overall burden of the disease is still increasing, particularly in developing countries (Morgan et al., 2023), this presents a major challenge for the clinical management of CRC. Genetically, colorectal cancer (CRC) can be genetically divided into two main types: hereditary and sporadic. Hereditary CRC primarily includes familial adenomatous polyposis (FAP) and Lynch syndrome. Sporadic CRC, which accounts for approximately 75% of cases, is mainly caused by gene mutations triggered by environmental factors. The occurrence and progression of sporadic CRC frequently involve the inactivation of genes such as APC, DCC, and TP53, over-expression of mutations in genes like KRAS, PIK3CA, and BRAF, as well as deletions in DNA mismatch repair genes. Most cases of CRC cases follow the “adenoma-cancer” sequence of progression, it takes between 5 and 10 years for an adenoma to advance to cancer (Zhu et al., 2020; Sun et al., 2024). Treatment for CRC mainly includes surgical resection, alongside and radiotherapy. However, 25%–30% of patients have metastasis when their initial diagnosis, and 50% of patients experience recurrent metastasis within 5 years of surgery (Ciardiello et al., 2022). Patients diagnosed with advanced CRC face many limitations, such as resistance to chemotherapy and serious adverse reactions. In-depth studies on molecular subtypes have greatly improved the 5-year survival rate of patients receiving molecularly targeted drugs (Ciardiello et al., 2022), such as drugs targeting vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) and epidermal growth factor receptor (EGFR) (Xie et al., 2020). Such studies have also improved the prognosis of patients by detecting their microsatellite instability/mismatch repair (MSI/MMR) and programmed death ligand 1 (PD-L1) status and adding immunotherapy (André et al., 2025). Current pharmacological interventions for CRC primarily focus on single-target agents; however, the therapeutic efficacy of drugs inhibiting individual signaling pathways or biological targets remains limited. In contrast, Traditional Chinese Medicine (TCM) and its bioactive components exhibit distinct advantages through their multi-target, multi-pathway, and multi-effect regulatory mechanisms (Chen et al., 2023; Gou et al., 2023). These compounds can markedly alleviate clinical symptoms, improve quality of life, and stabilize lesions in patients with CRC. In addition, when used in combination therapies, these compounds can enhance treatment outcomes and minimize adverse effects.

Herba Patriniae, a wild plant with recognized medicinal and dietary value, has been utilized for over 2,000 years. It is derived from Patrinia scabiosaefolia or Patrinia villosa of the Valerianaceae family, with its rhizomes, roots, and entire herba employed for therapeutic purposes. Widely distributed across tropical and subtropical regions, Herba Patriniae is rich in bioactive compounds, such as triterpenes, saponins, iridoids, and flavonoids; remarkably, Patrinia villosa contains more flavonoids (Gong et al., 2021). These constituents contribute to its diverse pharmacological properties, including antioxidant, anti-tumor, anti-inflammatory, antimicrobial, and antiviral activities, making it a promising candidate for drug development (Li et al., 2018; Huang et al., 2019; Zou et al., 2021; Liu et al., 2023a; Li K. et al., 2024).

Recently, many studies have supported the efficacy of Herba Patriniae in preventing and treating CRC, although the underlying mechanisms of action remain unclear. The anticancer compounds of this plant have shown significant interactions with target proteins involved in the progression of CRC (Qi et al., 2020). Studies have suggested that Herba Patriniae acts through several signaling pathways to inhibit CRC, with its high flavonoid content playing a pivotal role. These flavonoids suppress cell proliferation (Zhang M. et al., 2015; Yang et al., 2023), induce apoptosis (Liu et al., 2013), mediate cell cycle arrest (Zhang M. et al., 2015), suppress angiogenesis in the tumor microenvironment (Chen et al., 2013), and ameliorate drug resistance (Huang et al., 2019). Despite their potent bioactivity, flavonoids, as polyphenolic compounds, generally have poor oral bioavailability, with only minimal metabolites detectable in urine and blood. Their interaction with gut microbiota is a critical mechanism underlying their biological activity (Liu et al., 2023b). Building on these findings, we reviewed the findings of clinical and preclinical studies focused on effective flavonoids in Herba Patriniae and unraveled their molecular mechanisms in CRC. This review provides a foundation for the development of anticancer small molecules derived from Herba Patriniae and help identify their potential therapeutic targets.

Flavonoids, a class of polyphenolic compounds, have a chemical structure composed of 15 carbon atoms, including two benzene rings (A ring and B ring) and an oxygen-containing ring (C ring). The basic structure of flavonoids is generally C₁₅H₁₀O₂, although their molecular formula vary based on their substituent groups. Structural diversity among flavonoids arises from substitutions on the A, B, or C rings, such as amino, methyl, hydroxyl, or glycosyl groups, resulting in derivatives with distinct biological activities (Zhang et al., 2007; Lotito et al., 2011). With a deeper understanding of the role of gut microbiota, studies have shown that flavonoid metabolism in the body relies not only on liver enzyme systems but also on gut microbiota. Through processes such as hydrolysis, reduction, and metabolic transformation, gut microbiota modifies the structure of flavonoids, enhances their biological activity, and affects their bioavailability and pharmacological properties (Kumar Singh et al., 2019; Landete, 2022). Epidemiological studies have indicated that higher flavonoid intake and serum levels are associated with a lower risk of colorectal inflammation and CRC (Chang et al., 2018). Based on an analysis of the TCM pharmacology database, we identified 13 flavonoid compounds from 52 active ingredients in Herba Patriniae that have been widely studied for their anticancer properties (Table 1, https://www.tcmsp-e.com/). A comprehensive understanding of the pharmacological effects of these flavonoids on CRC is critical for advancing therapeutic strategies.

Crypts are deep grooves formed by epithelial cells in the colon. Abnormal crypt foci (ACF) appear when these crypts undergo significant morphological changes, such as hyperplasia, irregular shapes, or abnormal cell differentiation. ACF are one of the earliest precancerous lesions in CRC. Early detection and effective intervention can significantly reduce the risk of CRC.

Flavonoid compounds can effectively prevent ACF. For example, the number of abnormal crypts in the colons of stressed mice was significantly reduced after treatment with quercetin (Ritter and Dinh, 1992; Matsukawa et al., 1997; Volate et al., 2005). Interestingly, in an obesity-related carcinogenesis model, quercetin significantly inhibited precancerous lesions and reduced serum leptin levels. Furthermore, in vivo studies revealed that quercetin markedly suppressed the expression of leptin mRNA in differentiated 3T3-L1 mouse adipocytes. These findings suggest that quercetin has the potential to inhibit colorectal cancer induced by obesity (Miyamoto et al., 2010). In the mice model of AOM-induced CRC, a 0.5% quercetin diet effectively inhibited intestinal lesions (Tutino et al., 2018). Similarly, a diet containing 0.1% apigenin reduced the number of high-magnitude ACF (defined as > 4 abnormal crypts per focus) by 57% (P < 0.05) (Au et al., 2006; Leonardi et al., 2010). Luteolin (1.2 mg/kg/day) mitigated AOM-induced intestinal oxidative damage by reducing lipid peroxidation, enhancing antioxidant defenses, and suppressing the formation of precancerous lesions (Ashokkumar and Sudhandiran, 2008). In the APC^Min/+ mouse model, apigenin dose-dependent inhibited tumor growth by phosphorylating the p53 protein in tumor tissue, thereby regulating tumorigenesis (Zhong et al., 2010). Treatment with kaempferol reduced tumor burden, restored impaired intestinal barriers, and downregulated the expression of Ki67 and LGR5 in APC^Min/+ mouse model (Li X. et al., 2022). However, rutin exhibited no preventive effect in the AOM-induced mouse model, likely due to its low intestinal bioavailability. Improving the solubility of rutin using solid dispersion technology and formulating it into frankincense-based compression-coated tablets enhanced its efficacy in inhibiting the development of CRC in vivo (Ismail et al., 2023).

Chronic inflammation is a significant risk factor for CRC, as it promotes cancer cell proliferation, invasion, and metastasis by modulating the tumor microenvironment, activating oncogenes, immune evasion, and dysbiosis (Yaeger et al., 2016; Chen et al., 2024). Apigenin has been shown to effectively inhibit inflammatory bowel disease (IBD) and colitis-associated cancer (CAC) in mice (Ai et al., 2017). Similarly, vitexin mitigated AOM/DSS-induced chronic colitis-associated carcinogenesis in mice (Chen et al., 2021). Linarin (25 or 50 mg/kg/day) significantly reduced myeloperoxidase activity in the colon and downregulated pro-inflammatory cytokines, such as TNF-α and IL-1β, while upregulating the anti-inflammatory cytokine IL-10. This effect alleviated DSS-induced intestinal damage and the function of the mucosal and intestinal barrier (Jin et al., 2022). In a TNBS-induced experimental colitis model in Wistar rats, morusin (12.5 mg/kg) showed comparable efficacy to sulfasalazine (50 mg/kg) in suppressing inflammation (Vochyánová et al., 2017).

In a CRC metastasis models, quercetin (Kee et al., 2016) and luteolin (10 or 50 mg/kg) significantly reduced the number and volume of lung metastases induced by CT26 cells (Kim H. Y. et al., 2013). Moreover, luteolin (IC50 = 5.9 μM, indicating relatively low anticancer activity) suppressed CT26-induced liver metastasis of colon cancer by 24% (Naso et al., 2016).

A prospective cohort study involving 87 patients, consisting of 36 patients who underwent CRC surgery and 51 patients who underwent adenoma polypectomy, investigated the preventive effects of a flavonoid mixture (20 mg apigenin and 20 mg epigallocatechin gallate) on tumor recurrence. After 3–4 years of colonoscopy follow-up, the group receiving the flavonoid mixture exhibited a tumor recurrence rate of 7% (1/14, 1 adenoma) compared to a 47% recurrence rate (7/15, including 3 tumor recurrence and 4 adenomas) in a matched untreated control group of patients with CRC (n = 15). These findings suggest that long-term treatment with flavonoids can reduce the recurrence rate of colorectal tumors in patients undergoing surgery (Hoensch et al., 2008). A 4-year nutritional intervention trial featuring a low-fat, high-fiber, high-fruit, and high-vegetable diet found that the intake of flavonoids, such as isoquercitrin, kaempferol, and quercetin, was associated with decreased serum levels of IL-6 and a lower recurrence rate of high-risk adenomas. This finding suggests a potential correlation between flavonoid intake and a decreased risk of adenoma recurrence (Bobe et al., 2010).

Patients with familial adenomatous polyposis (FAP) suffer from a high risk of CRC. In a small clinical study, 6 months of combined treatment with curcumin and quercetin after CRC surgery led to a 60% reduction in the number and size of polyps in the ileum and rectum compared to baseline, indicating that the potential of this combination therapy in reducing polyp burden in patient with FAP (Cruz-Correa et al., 2006).

A Phase I clinical study on quercetin’s resistance and pharmacokinetics revealed the safety of intravenous quercetin. At a specific plasma concentration, it inhibited the activity of lymphocyte tyrosine kinase, showing anti-tumor effects. In nine patients with CRC, treatment with intravenous quercetin for 1 hour suppressed the phosphorylation of serum lymphocyte protein tyrosine for 16 h. Additionally, in a patient with cisplatin-resistant ovarian cancer, treatment with quercetin (420 mg/m²) reduced CA125 levels from 295 units/mL to 55 units/mL. Similarly, another patient with liver cancer showed decreased serum alpha-fetoprotein levels after treatment (Ferry et al., 1996).

However, a large retrospective clinical study with 38,408 participants assessed flavonoid intake using dietary questionnaires and found no significant association between the intake of five common flavonoids (quercetin, kaempferol, myricetin, apigenin, and luteolin) or flavonoid-rich foods and CRC prevention (Wang et al., 2009). This lack of correlation may be attributed to the low flavonoid content in typical diets, antibiotic use, poor dietary habits, etc.

Although Herba Patriniae is widely used in clinical practice and its flavonoid compounds exhibit anti-CRC activity (Table 2), there is currently no large-scale clinical research supporting their efficacy. And most existing clinical studies used the combined administration of two or more flavonoid compounds. Systematic clinical evaluations of flavonoid interventions targeting for CRC pathological diversity and mutational heterogeneity are notably absent in current literature. Future research should also focus on the effective dosage and safety of individual flavonoid compounds from Herba Patriniae.

The majority of colorectal cancer cases follow the classical adenoma-carcinoma sequence: normal colonic epithelium -adenomatous polyp–adenocarcinoma (Li et al., 2021). This carcinogenic progression begins with a mutation in the APC gene, followed by further mutations in KRAS, TP53, DCC and other critical genes (Schumacher et al., 2015). CRC pathogenesis involves the dysregulation of multiple pivotal signaling pathways: The Wnt/β-catenin pathway promotes tumor cell proliferation and differentiation, the PI3K/AKT pathway enhances cancer cell growth, survival, and metabolic adaptation, and the RAS/RAF/MEK/ERK cascade drives cell cycle progression and aberrant proliferation. In contrast, the transforming growth factor-β (TGF-β) pathway exhibits tumor-suppressive effects in the early stages, but promotes tumor invasion and metastasis through epithelial-mesenchymal transition (EMT) in the advanced stages of the disease. Current evidence demonstrates that flavonoids can effectively suppress CRC progression through multi-target mechanisms and the coordinated modulation of these oncogenic pathways (Li Q. et al., 2024).

Gut microbiota plays a crucial role in the progression of CRC, and targeting gut microbiota is an important pharmacological strategy for treating CRC (Jia et al., 2024). Flavonoids are not easily absorbed by the human body after oral intake. Most flavonoids are metabolized by gut microbiota into smaller, more absorbable active metabolites, thus enhancing their bioactivity.

Gut microbiota can transform flavonoids by altering their chemical structure and biological functions, thereby enhancing their anticancer potential (Figure 3). Specific bacterial strains, such as Bifidobacterium and Lactobacillus, play essential roles in this metabolic process. Flavonoids mainly exist as glycosides, with only 5%–10% being directly absorbed, resulting in low bioavailability. The majority of flavonoids are metabolized by gut microbiota into smaller molecules, such as phenolic acids, which increases the abundance of beneficial bacteria and stimulates the production of short-chain fatty acids (SCFAs) (Gonzales et al., 2015; Feng X. et al., 2018). C-glycoside flavonoids are highly metabolized in the gut. For example, enzymes expressed by Caco-2 cells can cleave C-C bonds in vitro, breaking the bonds between sugar and aglycone residues in orientin and isoorientin to produce glucuronidated or sulfated derivatives of luteolin and apigenin (Dihal et al., 2006; Tremmel et al., 2021). Studies have shown that Bacillus glycinifermentans, Flavonifractor plautii, Bacteroides eggerthii, Olsenella scatoligenes, and Eubacterium eligens can degrade quercetin. B. glycinifermentans produces metabolites like 2,4,6-THBA and 3,4-DHBA, which inhibit the proliferation of CRC cells (Sankaranarayanan et al., 2021). 3,4-Dihydroxyphenylacetic acid, a microbial metabolite derived from quercetin, was shown to strongly inhibit the CRC-promoting properties of heme chloride than quercetin itself and prevent heme-induced malignant transformation of colonic epithelial cells and mitochondrial dysfunction (Catalán et al., 2020). The metabolism of flavonoids is a complex process involving various gut microbiota, which can sustain or even enhance their anticancer effects (Zhang et al., 2014; Cattivelli et al., 2023).

On the other hand, flavonoids can regulate the composition of gut microbiota by promoting the growth of beneficial bacteria and inhibiting the proliferation of pathogenic and pro-inflammatory bacteria. In a mouse model of cancer, luteolin has been shown to significantly reduce the abundance of disease-associated or inflammation-associated genera, such as Clostridium UCG-014 and Turicibacter, while increasing the abundance of Muribaculaceae, a health-promoting genus. This finding supports its antitumor effect through microbiota modulation (Pérez-Valero et al., 2024). Similarly, apigenin can mitigate gut dysbiosis by increasing the abundance of beneficial bacteria, such as Lachnospiraceae, Muribaculaceae, and Bifidobacterium (Rithidech et al., 2024), and affecting the growth and gene expression of Enterococcus (Wang et al., 2017). Interestingly, the anticancer effects of apigenin relied on gut microbiota (Bian et al., 2020). Isoorientin has significant advantages in preventing colon damage and gut dysbiosis induced by benzo [a]pyrene (BaP). Isoorientin was found to changes the abundance of gut microbiota, especially Feacalibaculum, Lactobacillus, Acetobacter, Desulfovibrio, and Alistipes, after exposure to BaP. Isoorientin also improves metabolic disorders of gut microbiota after exposure to BaP. Particularly, it improved perturbations in pathways involving LPS and sulfur compounds (He et al., 2019). Linarin reversed DSS-induced gut microbiota dysbiosis, affecting the abundance of different genera, such as Alistipes, Rikenella, and Clostridia UCG-014_norank. It also increased the abundance of SCFA-producing bacteria, like Lactobacillus, Roseburia, Parabacteroides, and Blautia (Jin et al., 2022).

Dysbiosis of gut microbiota can affect the production of metabolites, such as bile acids (BAs), LPS, choline, and SCFAs. Quercetin can modulate the composition of gut microbiota, improve the integrity of the intestinal barrier (Mohammadhasani et al., 2024), and reduce serum levels of hippuric acid (HA), a polyphenol-derived metabolite, observed in patients with Crohn’s disease. HA levels in the gut were found to be positively correlated with polyphenol intake, the abundance of flavonoid-degrading bacteria, and SCFA production (Xiang et al., 2024). Kaempferol can increase the expression of enzymes such as sterol CYP27A1 and sterol CYP8B1, thereby increasing the decreased levels of CDCA and 12α-hydroxylated bile acids and upregulating FXR expression. This finding suggests that kaempferol can downregulate secondary bile acid synthesis pathways, increase G-protein-coupled receptor activity, and decrease NLRs activity, thereby influencing cell differentiation, proliferation, survival, and apoptosis (Li X. et al., 2022). However, further exploration is needed to fully explore the mechanisms through which flavonoids interact with gut microbiota and their metabolites.

Through their bidirectional interaction with gut microbiota, flavonoids promote gut health and inhibit the development of CRC. They are transformed into more active metabolites and modulate the composition of gut microbiota, resulting in anti-inflammatory, antioxidant, and immunomodulatory anticancer effects in cancer. This interaction provides new insights and research directions for the prevention and treatment of CRC.

Flavonoids have shown significant potential in the prevention and treatment of CRC. However, their poor water solubility limits both their bioavailability and therapeutic efficacy. Additionally, the metabolism of flavonoids can further reduce their bioavailability and diminish their therapeutic potential. Nanomaterials offer unique advantages in targeted drug delivery. They can protect drugs against degradation, enhance drug solubility, reduce toxicity, and enhance pharmacodynamics and pharmacokinetics. The application of nano-engineered flavonoids not only improves the antitumor effects of chemotherapy drugs but also reduces their systemic toxicity (Table 3).

Quercetin, for example, exhibits low solubility in neutral and hydrophilic fluids. Encapsulation with soybean polysaccharide and chitosan has been shown to enhance the stability and solubility of quercetin-loaded flavonoids. Multiple independent studies have confirmed that quercetin-nanocarriers can improve their pharmacokinetics and absorption, thereby enhancing their anticancer efficacy against CRC. For instance, encapsulating quercetin in nanocapsules potentiated its antioxidant and cytotoxic activity in HT-29 and HCT116 cells (Jain et al., 2023). Additionally, the co-administration of quercetin with nanosynthesized drugs revealed improved antitumor efficacy (Colpan and Erdemir, 2021).

Flavonoids also exhibit antioxidant properties by chelating transition metals involved in free radical generation. Metal-flavonoid complexes act as more potent free radical scavengers than isolated flavonoids. For example, a quercetin-ruthenium complex reduced HT29 cell proliferation and induce tumor cell apoptosis by upregulating p53 and Bax and downregulating Bcl2 expression. The radical scavenging ability and antimicrobial activity of isoorientin-Zn were significantly stronger than those of isoorientin alone (Wang et al., 2021). Furthermore, the use of microencapsulated Bifidobacterium bifidum and Lactobacillus gasseri, either alone or in combination with quercetin, inhibited of CRC progression in Apc^Min/+ mice (Benito et al., 2021).

Apigenin nanoformulations have been applied for targeted tumor cell treatment. Nano-encapsulation of apigenin enhanced cellular uptake, pro-apoptotic effects, and bioavailability in mouse blood and colonic mucosa (Dutta et al., 2018; Amini et al., 2021; Hong et al., 2022). Liposomal nanocarriers of apigenin exhibited anti-angiogenic properties, reduced cell proliferation, and increased cell apoptosis. Preclinical trials using these formulations in nude mouse xenograft models revealed enhanced antitumor effects (Sen et al., 2019). Luteolin has low oral bioavailability due to its poor water solubility, which maks its intravenous or intraperitoneal administration impossible. Nanoformulations help overcome these challenges, improving the anticancer efficacy of luteolin.

The flavonoids found in Herba Patriniae possess extensive anti-tumor properties, and their therapeutic effects in CRC have gained significant attention. These flavonoids show great promise for the development of new therapeutic agents.

Regarding pharmacological mechanisms, current studies suggest that flavonoids exert anti-tumor effects through various pathways (Figure 4). For instance, it was shown that flavonoids can reduce ACF, regulate cell cycle, inhibit the growth and proliferation of CRC cells, promote apoptosis, and suppress EMT, reversing CRC resistance, and modulate the composition of gut microbiota. A growing number of studies have focused on the crucial role of the tumor microenvironment (TME) in cancer progression. Recent findings unveiled that flavonoids from Herba Patriniae can affect the TME, including macrophage phenotypes. However, most studies have primarily observed the effects of flavonoids on stromal cells, and a deeper understanding of their mechanisms of action is still needed.

Well-designed randomized controlled trials are needed to confirm the safety and efficacy of flavonoid-based therapies. Although Herba Patriniae is widely consumed in tropical and subtropical regions, few clinical trials have administered Herba Patriniae and its flavonoids to patients with CRC. Such studies should evaluate the safety and tolerability of Herba Patriniae, and determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). High-quality Phase II–III clinical studies can provide higher-level evidence regarding efficacy. In addition, large-scale longitudinal interventional studies are important for understanding the metabolic variability of flavonoids for developing personalized therapeutic strategies based on gut microbiota.

Low bioavailability is also a major obstacle limiting the clinical application of flavonoids in Herba Patriniae. However, the development of novel nanoformulations holds promise for improving drug delivery, targeting specific tissues, and enhancing the bioavailability of these compounds. Modifying flavonoids based on their mechanisms of action can also advance the therapeutic use of natural plant compounds in the treatment of CRC.

Although some progress has been made in understanding the interaction between gut microbiota and flavonoid metabolites, there are many unknown aspects. The ability of gut microbes to metabolize flavonoid and the specific metabolites involved in the pathogenesis of CRC are still poorly understood, with limited data from clinical samples. More evidence from sterile mouse models and clinical studies is needed to address these gaps and explore the specific mechanism.