Traditional Chinese medicine Qingjie Fuzheng granules (QFGs), consisting of malt, Scutellaria barbata D. Don, Hedyotis diffusa Willd, and Astragulus, showed the function of inhibiting proliferation and inducing apoptosis at concentrations of 0.5–2.0 mg/mL. QFGs increased the expression level of Bax, Fas, and Fasl, decreased Bcl-2 levels, and stimulated activation of caspase-3/8/9 in HCT-116 and HCT-8 cell. This study showed that QFGs induced apoptosis via the mitochondria-dependent pathway and the death receptor apoptosis pathway in two types of CRC cells (Yang et al., 2019). Tang et al. conducted an experiment that differed from the Qingjie Fuzheng granule study. The experiment selected four CRC cells and found that the Sanjie Yiliu formula (SJYLF) significantly inhibited the activity of HCT-8, SW480, HT29, and DLD-1 CRC cells. SJYLF components, consisting of Fabanxia, Glabrous Sarcandra herb, Thunberg Fritillary bulb, and ground beetle species, initiated apoptosis through downregulating Bcl-2, cylin D1, and CDK4 protein, as well as increasing Bax expression (Tang et al., 2021). Besides, Sijunzi decoction (SJZD) consistsing of Panax ginseng C.A.Mey., Atractylodes macrocephala Koidz., Poria cocos Wolf., and Glycyrrhiza uralensis Fisch., proportioned at a ratio of 2:2:2:1 and clinically used in treating CRC. Experimentally, SJZD could induce apoptosis and autophagy of CRC cells via PI3K/Akt/mTOR pathway. This article analyzed the function of SJZD through network pharmacology technology and experimental in vivo and vitro (Shang et al., 2023). The PI3k/AKT pathway can regulate the proliferation and cycle of tumor cells, promote tumor angiogenesis, facilitate tumor invasion and metastasis, and regulate apoptosis (Dong S et al., 2022). Zhang and others, being similar to the previous of SJZD experiment, discovered 286 bioactive compounds and 130 potential therapeutic targets in the ethanolic extract of gastric tonic. They demonstrated that Wei-Tong-Xin induces colon cancer cell apoptosis by activating the PI3K/AKT pathway instead of iron death in HCT116 cells. The western blot analysis revealed increased expression of Bax, caspase 3, and caspase 9, and decreased expression of BCL-2. Additionally, Zhang and others conducted in vivo mouse experiments to validate the apoptotic role of Wei-Tong-Xin in colorectal cancer. They also confirmed the apoptotic effect of Wei-Tong-Xin on colorectal cancer through in vivo mouse experiments (Lin et al., 2023). Contrast to the previous western blot analysis, Weichang’an formula (WCAF) plays an important role in inducing CRC apoptosis through TUNEL assay. And the treatment group of WCAF decreases the expression of Leptin, VEGF-A and VEGFR-1 (Pan et al., 2020).

Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) comprises Coix lacryma, Radix et Rhizoma Pinelliae and Radix et Rhizoma Bianchi, three Chinese herbs combined in a 30:6:15 ratio. It is commonly administered for the treatment of gastrointestinal tumours. YYFZBJS, at concentrations of 30 µg/mL, 60 µg/mL, and 90 µg/mL, significantly decreased the expression of CDK1, p-AKT, and p-PI3K proteins in HCT116 and SW480 cells. This finding proves that by regulating the CDK1/PI3K/AKT pathway, inducing apoptosis and blocking the cell cycle, YYFZBJS effectively inhibits the proliferation of CRC. The efficacy of YYFZBJS on proliferation was validated by establishing the AOM/DSS mouse model (Li J et al., 2022). In an identical study, Xiang et al. conducted a network pharmacological analysis to screen four active ingredients from the YYFZBJS recipe. These four active ingredients were identified using high-performance liquid chromatography and were included in the HT-29 cell culture medium. The study found that the four active ingredients efficiently inhibited the growth and induced apoptosis of CRC cells by regulating TLR4/NFBJS (Xiang et al., 2022).

Metastatic cases of CRC can be detected at initial diagnosis in 20%–25% of CRC patients (Piawah and Venook, 2019). CRC patients drops to 14% after metastasis for 5-year survival rate (Siegel et al., 2023). Metastasis of tumors poses a significant challenge in the current treatment of CRC. Studies have confirmed that angiogenesis is a key factor in tumor metastasis, and vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis (Sakata and Larson, 2022). Lu Zhao et al. administered a safe clinical Chinese medicine, Xiaoyaosan, to C57BL/6J mice in an aqueous solution of 1516.67 mg/kg through gavage for 7 days. HT-29 colon cancer cells were then injected into the spleen of mice in order to establish a liver metastasis model of C57BL/6J colon cancer, and they continued to receive the treatment for 21 days. The study found that the Xiaoyaosan group had a significant inhibitory effect on liver metastasis of colon cancer by reducing the expression of VEGR and CD31 in liver metastatic tissues (Zhao et al., 2020). In addition, tumor cells can interact with the extracellular matrix, creating a pipeline system that transports blood, also known as angiogenic mimicry. This process leads to remodeling of the tumor microenvironment and is related to metastasis and prognosis (Wang et al., 2017). Zong et al. established a nude mouse model of lung metastasis by administering an Astragalus Atractylodes mixture, 16 mg/g, by gavage for 50 days. Zong found that the number of instances of lung metastasis in the Astragalus Atractylodes mixture group was significantly lower. The result showed that the mixture of Astragalus Atractylodes effectively inhibited CRC angiogenesis mimicry and migration of HCT116 and LOVO cells (Zong et al., 2020). Sini decoction (SND) consists of Fuzi, Zhigancao and Ganjuang, limiting CRC liver metastasis and upregulating IL-2 and IFN-γ. The effective of SND is associated with PI3K-Akt, EGFR and HIF-1 signaling pathway (Chen J et al., 2023).

The Jianpi Jiedu Recipe is a traditional Chinese medicinal compound derived from clinical practice that has found extensive use in treating gastrointestinal tumors. C57BL/6 mice were injected with 10 µg/100 µL Jianpi Jiedu Recipe into the tail vein every other day for 3 weeks, followed by an intra-splenic injection of MC38 colorectal cancer cells. The study revealed that Jianpi Jiedu Recipe effectively inhibits colorectal cancer metastasis by suppressing the extracellular vesicle-mediated expression of ITGBL1, inhibiting the TNFAIP3-NF-kB pathway activity, and subsequently reducing the activation of CAFs (Li R et al., 2022). Compared to regulate TNFAIP3-NF-kB pathway activity, a novel research shows that chanling Gao (CLG), a Chinese medicine formula, can limit CRC metastasis and reduce MMP-2 and MMP-9 expression in tumors. The result indicate that CLG regulate the PI3K/Akt/mTOR signaling pathway to inhibit metastasis of CRC (Chen et al., 2024).

The gut microbiota is a highly complex system that regulates innate and adaptive immunity. Disruption of gut microbiota can result in the procession of colorectal cancer (Jain et al., 2021). Patients with CRC often have dominant gut microbiota consisting of certain germs such as Escherichia coli, Bacillus fragilis, and Clostridium nucleatum. These pathogenic bacteria interfere with the immune surveillance mechanism by impairing intestinal mucosal immunity, promoting CRC development (Clay et al., 2022). Pien-Tze-Huang (PZH) can deplete pathogenic bacteria Peptoniphilus harei, Campylobacter jejuni, Collinsella aerofaciens and Aeromonas veronii in AOM/DSS mice and Apcmin/+ mice. At the same time, PZH inhibited tumorigenesis of CRC through increasing the abundance of probiotics Eubacterium limosum and Pseudobutyrivibrio xylanivorans (Gou et al., 2023).

Xiaoai Jiedu Recipe (XJR) is a kind of traditional Chinese medicine prescription for the treatment of colorectal cancer. 5 g/kg and 20 g/kg of XJR was used to treat CRC in xenograft model of mice by gavage for 14 consecutive days. Using 16s rRNA gene sequencing, the XJR dosing group decreased the abundance of Prevotellaceae, Bacteroides and Bacteroidetes. Studies demonstrated that XJR can inhibit the development of CRC in mice by modulating gut microbiota (Qiu et al., 2023).

Compared to the xenograft model of mice, Sui Hua et al. chose C57BL/6J-APCmin/+ mice to investigate the role of Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS). This study used healthy controls and feces from volunteers receiving YYFZBJS to gavage APCmin/+ mice for 12 weeks. Contrasted to the healthy control group, mice receiving feces from volunteers receiving the drug had a reduced number of intestinal tumors, and gut microbiota was significantly regulated, as evidenced by an increase in the fractionation of Bifidobacterium and Prevotellaceae and a decrease in the abundance of Bacteroides, Lachnospiraceae, and Dubosiella. The altered gut microbiota mediated by YYFZBJS repressed CRC cell growth (Sui et al., 2020).

Feng et al. chose the AOM/DSS mouse model to conduct their study to explore Wu Mei Wan’s mechanism. Wu Mei Wan (WMW) was derived from the Treatise on Typhoid Fever and can treat abdominal pain and dysentery. The results indicated that after WMW intervention, the abundance of Bacteroidetes decreased, and that of Firmicutes increased at the phylum level. Additionally, the abundance of Bacteroidales_s24-7_group decreased, while that of Lachnospiraceae increased at the family level. WMW regulated NF-kB/IL-6/STAT3 pathway to balance between tumor-promoting and tumour-suppressing bacteria, thereby attenuating CAC (Jiang et al., 2020). Contrast to NF-kB/IL-6/STAT3 pathway, Anchang Yuyang Decoction (AYD) can regulate PPAR signaling pathway in CRC. AYD treatment group showed that the relative abundance of genera decreaesed, including Romboutsia, Monoglobus, norank_f_Oscillospiraceae, norank_f_ruminococcaceae, and other generas upregulated, such as norank_f_Muribaculaceae, Bacteroides, unclassified_f_Prevotellaceae, and Alistipes (Wei et al., 2024). Above all, there is a great importance to regulate the intestinal flora. The balance of intestinal flora is related to CRC. The application of prescriptions in CRC has benefit on the balance of intestinal flora, so that it can effectively treat CRC.

Autophagy is a free cellular mechanism of action to maintain homeostasis in response to various external stimuli, and in the case of tumours, excessive autophagy leads to autophagic cell death by degrading the cytoplasm beyond recovery (Mariño et al., 2014). The polysaccharide-depleted fraction of DangguiBuxue Tang (DBT) induced autophagy-associated cell death of CT26, sensitizing to chemotherapy and radiotherapy treatment and inhibiting the growth of CRC (Chen et al., 2016). What’s more, T33 is composed of five traditional Chinese herbs, namely, Kansui Radix, Glycyrrhizae Radix et Rhizoma Praeparata cum Melle, Paeoniae Radix Alba, Pinelliae Rhizoma Praeparatum Cum Zingibere et Alumine, and Rhei Radix et Rhizoma. T33 inhibits CRC activity by promoting autophagy, increasing Atg7, Atg5, and Beclin-1 proteins in HT-29 and Caco2 cells (Liu et al., 2022). Banxia Xiexin decoction (BXD) promoted ferritinophagy in CRC cells. BXD increased the ratio of LC3 II/LC3 I and NCOA4, and reduced the levels of FTH1 and GPX4 through suppression of the PI3K/AKT/mTOR axis (Wang et al., 2024).

Besides, inflammation and oxidative stress-induced carcinogenesis play significant part in the progression of CRC (Balmus et al., 2016). Jianpi Yiqi decoction is a commonly used treatment for gastrointestinal ailments like gastritis and colitis. Research found a significant decrease in IL-6 and TNF-a in venous blood, indicating that Jianpi Yiqi decoction has excellent anti-inflammatory properties and significantly reduces inflammatory responses. This result shows that good clinical efficacy was reflected in treating CRC patients through using Jianpi Yiqi prescription (Yang et al., 2023). It’s related to inflammatory in the next research which includes Huoxiang Zhengqi (HXZQ) significantly to reduce inflammation and oxidative stress in colitis-associated cancer by regulating Nrf2/NF-kB/NLRP3 pathway (Dong M et al., 2022). Compared with the study of HXZQ, ShaoYao decoction (SYD) also can activate the Nrf2 pathway, upregulating the expression of downstream Nrf2 genes and attenuating oxidative stress in AOM/DSS model mice. SYD can prevent and treat the ulcerrelated colorectal cancer (Wang X et al., 2020).

Additionally, we can’t aviod to mention the importance of the tumor microenvironment. A lot of researches found tirelizumab (TLzmab) resulted in imbalance of tumor immune microenvironment during treating CRC. Shenling Baizhu Decoction (SLBZD) can increase M1 macrophages and decrease M2 macrophages and Treg cells in the tumor immune microenvironment. Thus SLBZD has exerted the synergistic effect of TLzmab for maintaining the balance of microenvironment (Deng et al., 2024). Compared to regulate the macrophages in the microenvironment, Bazhen Decoction (BZD) can increase the ratio of CD4+T cells to CD8+T cells in the spleen and tumor tissues, downregulate the PD-1 expression on T cell surfaces. The study indicated BZD treated CRC through regulating tumor immune microenvironment (Lu et al., 2023). Thus, the prescriptions of TCM can also treat CRC through diversity mechanisms, which are potential targets to explore.

The trametes robiniophila murr (Huaier) were extracted with 95% anhydrous ethanol. Huaier extract improved the severity of tumorigenesis of CRC, reducing tumor number, size and load. After using Huaier, the apoptosis-associated protein levels, such as P53, Bax, and Bcl-2, showed significant differences. The results demonstrated that huaier extract suppressed cell proliferation and induced apoptosis in HCT116 and HCT8 cells (Zou et al., 2020). Compared with 95% ethanol and water extracts, the 60% ethanol extract of Sanghuangporus vaninii significantly inhibited the AKT/mTOR signaling pathway, as well as induced cell apoptosis and blocked G2/M cell cycle (Guo S et al., 2022). Patrinia scabiosaefolia also regulates the AKT pathway. The ethanol extract of Patrinia scabiosaefolia significantly reduced HCT-8/5-FU cell number and apoptosis (Huang et al., 2019). Additionally, Sanguisorba officinalis L. (DY) was extracted by aqueous. The aqueous extract of DY can suppress cell proliferation and apoptosis via increasing the expression of Bax, cleaved-caspase3 and cleaved-PARP proteins and reducing Bcl-2 expression (Zhang W et al., 2022). Salvia miltiorrhiza belongs to the Salvia genus. Salvia miltiorrhiza was dissolved in 100% dimethyl sulfoxide (DMSO). This study was based on network pharmacology and molecular docking technology, showing that Salvia miltiorrhiza was related to three key targets: SRC, IL-6, and INS. In vitro experiments, Salvia miltiorrhiza inhibited the proliferation of CRC via inhibiting the INS/SRC/IL-6 pathway (Jiang and Xun, 2024).

What’s more, some researchers had different view about using herbs to treat CRC. Patrinia villosa Juss. (P.V) can reduce the levels of CRC biomarkers CEA, CA19-9 and CA72-4 via PI3K/Akt signaling pathway (Li X-C et al., 2023). Besides, many studies though that a hig-fat diet (HFD) accelerates the risk of CRC. Jin found that Aster glehni (AG) had anti-adipogenic effects in mice model. AG inhibited colitis-associated colon carcinogenesis in mice via preventing colon shortening and reducing the number of colorectal polyps though inhibiting STAT3 (Jin et al., 2020). Above all, numerous herbs and extracts of TCM have remarkable therapeutic effects in inducing apoptosis and inhibiting proliferation of CRC.

The hot water extract of Melissa officinalis (MO) has more effective anti-CRC activity. By modulating the epithelial-mesenchymal transition (EMT), MO can inhibit migration, proliferation, and trigger apoptosis of CRC (Kuo et al., 2020). Compared with the hot water extract, the ethyl acetate extract 3 (EA3) of Bolbostemma paniculatum (Maxim.) Franquet can effectively suppress the clone formation, invasion and migration of CRC by suppressing the PI3K/Akt pathway (Li Y et al., 2022). Besides, Asparagus (ASP) can regulate the PI3K/AKT/mTOR signaling pathway, inhibiting proliferation, invasion and migration of HCT116 and LOVO cells (Liang et al., 2022). A similar result showed that Scutellaria barbata D.Don (SB) can effectively inhibit the migration and invasion ability of HCT-8 cells in a dose-dependent manner via PI3K/Akt and TGF-β pathways. The ethanol extract of SB can reduce the expression of MMP-1, MMP2, MMP-3/10, MMP-9, and MMP-13. And E-cadherin and N-cadherin had no significantly difference in using the ethanol extract of SB (Jin et al., 2017). Beside, Sanguisorba officinalis Linn. (DY) can reverse EMT procession, so that inhibition cell metastasis. After DY treatment, the results showed that DY can reduce the expression of N-cadherin, vimentin and snail proteins, and upregulate E-cadherin expression via inhibition of the Wnt pathway (Zhang W et al., 2022).

Furthermore, when Angelica sinensis and OXA act in combination on HCT116 cells, the combinations show synergistic or additive effects. The expression levels of Ki67, MMP9, and CD206 in the Angelica sinensis group combined with OXA group were lower than those in the OXA group. The results suggest that Angelica sinensis can be used as an auxiliary drug in the treatment of colorectal cancer (Hao et al., 2022). More detailed information concerning anti-CRC of herbs is depicted in Table 2.

As we all known, 5-fluorouracil (5-FU) was the first-line cure of medicine in treatment CRC. But, the acquisition of chemotherapy drug resistance always caused of cancer treatment failure. Sanguisorba officinalis L. (DY) increased the susceptibility of 5-FU to drug-resistant CRC cells via the Ras/MEK/ERK and PI3K/Akt pathways (Zhang et al., 2023). Coupled with Sanguisorba officinalis L., Portulaca oleracea extract (POE) downregulate c-Myc and cyclin D1 expression, reducing gut microbiota imbalance through inhibiting the Wnt/β-catenin signaling pathway (Yi et al., 2022). What’s more, Curcumae longae Rhizoma can reverse CRC 5-Fu resistance by inactivating the TLR4/PI3K/AKT/mTORC1 pathway. Curcumae longae Rhizoma combined with 5-Fu can induce cell apoptosis by inhibiting bcl-2 and activating caspase-3 and Bax, thereby reversing 5-FU resistance (Teng et al., 2022). Additionally, Juniperus communis (JCo) is a well-known plant to treat cancer in traditional herbal medicine. The results showed that JCo, which was extracted by steam distillation, had a synergistic effect with 5-FU in CRC cells. In fact, the cell cycle played an important role in treating CRC. Jco extract can reduced cell cycle arrest to inhibit CRC growth (Lai et al., 2021).

Sun et al. found that berberine induced apoptosis and blocked the cell cycle at phase G0/G1 in HCT116 and SW480 with a dampened hedgehog pathway (Sun et al., 2023). As showed by the increase of the ratio of Bax/Bcl-2 and mitochondrial depolarization, Lycorine induced mitochondrial apoptosis by targeting the STAT3 pathway (Wu et al., 2018). Besides, Coptisine also activated mitochondrial apoptosis of HCT-116 by down-regulating pro-caspase 3, Bcl-2 and upregulating Bax, cytochrome c and cleaved caspase-3 expression (Han et al., 2018). Homoharringtonine regulated cyclinA2 and CDC2 in the Bcl-2 apoptosis pathway by inhibiting the PI3K/AKT pathway of Lovo cells. The study showed that Homoharringtonine significantly suppressed LoVo cell growth in vitro and in vivo (Shi et al., 2020).

Evodiamine inhibited the NF-κB pathway by binding to the α-helix of NF-κB, inhibiting colon cancer proliferation (Zhang Y et al., 2022). Scutellarin significantly ameiorated tissue apoptosis in the AOM/dss mouse model by inhibiting NF-κB and Hedgehog signaling axis (Zeng et al., 2022). Celastrol can also regulate the NF-kB/COX-2 signaling pathway, activate cysteine-dependent apoptosis, and promote G1 cell cycle arrest, thereby inhibiting the proliferation and inducing apoptosis of CRC (Zhang H et al., 2022). Genistein could effectively decrease the viability of HT29 and SW620 cells and found that intracellular NF-KB was translocated from the cytoplasm to the nucleus, which proved that genistein could decrease cell viability of colon cancer cells and inhibit the proliferation by increasing the oxidative stress and inflammatory response of colon cancer cells (Alorda-Clara et al., 2022).

Compared to inhibiting the NF-κB pathway, Chen et al. discovered that Matrine triggered apoptosis of HT29 and DLD1 by suppressing the miR-10b-5p/PTEN pathway (Cheng et al., 2022). Ginsenoside Rh2 inhibited Wnt pathway activity and inhibits cell proliferation/migration and colony formation (Li S et al., 2023). Besides, Fisetin induces apoptosis by down-regulating nuclear factor erythroid 2-related factor 2 (Nrf2) in CRC (Pandey and Trigun, 2023). In the same animal model, the study found that Hesperetin reduced the occurrence of CRC induced by 1,2-dimethylhydrazine in Wistar rats by inhibiting oxidative stress, enhancing antioxidant, anti-inflammatory and apoptosis effects (Hassan et al., 2023). Liu F et al. reported that the administration of curcumin significantly suppressed the size of xenograft tumors. Mechanistic exploration determined that curcumin can target miR-134-5p expression and regulate the CDCA3/CDK1 pathway, thereby inhibiting proliferation in CRC (Liu et al., 2023). Additionally, Other authors have established a zebrafish transplantation model and demonstrated that dendrobium polysaccharides, astragalus polysaccharides, and shiitake mushroom polysaccharides can effectively inhibit the growth of HT29 cells. Their mechanism of action may involve immune modulation and the induction of apoptosis in tumor cells (Tao et al., 2021).

Besides, Apigenin was positively correlated with pyruvate kinase M2 (PKM2) expression in LS-174T cells and HCT-8 cells. The characterized of Apigenin suppressed cell proliferation and increased of apoptotic effects (Shi et al., 2023). What’s more, Oridonin, a diterpenoid compound extracted from Rabdosia rubescens, has been indicated to inhibit the proliferation of CRC. Oridonin promoted CRC cell death, upregulating TP53, inhibiting TCF4 transactivation via inhibiting the TP53/TCF4 axis (Zhou et al., 2023).

Metastasis of colorectal cancer is a complex pathophysiological process that involves multiple factors and steps. One crucial factor is angiogenesis, which is necessary for primary tumour metastasis and is regulated by both pro-angiogenic and anti-angiogenic factors. Ginsenoside Rg3 (Rg3) has stereoselective activities to decrease the expression of vascular endothelial growth factor receptor 2(VEGFR2) and aquaporin1. Through response surface methodology, Rg3 can significantly suppress the loop formation and migration of human umbilical vein endothelial cell (HUVEC) (Nakhjavani et al., 2021). Polysaccharide (EPS1-1) dose-dependently suppressed the migration, invasion and adhesion abilities of CT26 cells. EPS1-1 dramatically inhibited the expression levels of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and microvessel density (MVD) in CT26 cells (Yu et al., 2018).

The components of TCM can effectively exert the inhibition of migration of CRC via multi-pathway. Quercetin can effectively suppress the migration and invasion of RKO cells through modulation of the JNK pathway (Trinh et al., 2022). Besides, Atractylenolide can affect PDK1/FoxO1, AKT/mTOR, and JAK/STAT3 pathways, inhibiting cancer cells’ proliferation, migration, and invasive ability (Li et al., 2020; Wang K et al., 2020; Sun et al., 2022). 8-gingerol, which is extracted from ginger, resulted in dose-dependent decrease in migration and invasion of CRC by targeting the EGFR/STAT/ERK pathway (Hu et al., 2020). Andrographolide has exhibited significant colorectal cancer activity by inhibiting the Src/MAPKs/AP-1 signaling pathways in a concentration-dependent manner (Yuan et al., 2018). Through cell heat shift experiments and drug affinity response target stability experiments, MAPK/APK2 plays a crucial role in Sophoridine inhibiting the growth and invasion of HCT116, SW480, and RKO(Wang et al., 2019). Bufalin, as the main active monomer of huachanshu, induced M2-type polarization and inhibited CRC metastasis via the SRC-3/IL-6 pathway (Tang et al., 2024). Rg1 also inhibited migration of CRC. Liu et al. found that the combination of rosmarinic acid (RA) and Rg1 can have anti-metastatic effects against CRC in regulating of PD-1/PD-L1 in CRC. Thus, Rg1 can inhibit the lung metastasis of CRC (Liu et al., 2024).

Besides, EMT was related to invasion and metastasis of tumor cells via inducing loss of cell-cell junctions and apicobasolateral polarity (Zhang N et al., 2021). Meng et al. found that liquiritigenin, a flavonoid extracted from the roots of Glycyrrhiza uralensis Fisch, downregulated the expression of Runx2 and inhibited PI3K/AKT to inhibit the invasion and EMT in HCT116 cell (Meng and Lin, 2019). What’s more, berberine treatment can inhibit mesenchymal epithelial transformation (MET) via reducing HEY2, E-cadherin, β-catenin and cyclin D1 (Ni et al., 2022). Besides, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), being a regulator of mitochondrial function, can promote ABCA1 expression to promote CRC metastasis through EMT. Chen et al. found that the natural compound Isoliquiritigenin (ISL), as an inhibitor of PGC-1α, targeted ABCA1 and reduced CRC metastasis by inhibiting EMT (W. Chen W et al., 2023). All in all, the components of TCM can effectively regulate multiple factors and steps of CRC to inhibiting migration, invasion and adhesion.

There are some different mechanisms, such as autophagy and ferroptosis, being implicated in the cell death of cancer cells (Gao et al., 2022). D3-3 stemming from sinomenine, is a new compound through synthesis and design. D3-3 apparently promote CRC cells to release the ferrous ion in autophagy-dependent manner (Zhu et al., 2024). On the other hand, Tangeretin regulated miRNA-21 to induce autophagy by synergizing with 5-Fluorouracil in CRC (Bai et al., 2022). As the same mechanism, quercetin also could regulate autophagy, and enhance the sensitivity of CRC for 5-FU via Drp-1-mediated mitochondrial fragmentation (Li et al., 2024). Kaempferol regulated the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis to overcome resistance to 5-Fu therapy (Wu et al., 2022). Solanine regulated the ALOX12B/ADCY4 molecular axis to induce typical ferropto in CRC cells. Simutaneously, solanine-induced ferroptosis is suppressed by silencing ALOX12B (Ma et al., 2024). Ginsenoside Rh3 triggered pyroptotic and ferroptotic cell death in CRC cells through the Stat3/p53/NRF2 axis while causing minimal damage to normal cells. These findings demonstrate remarkable anticancer potential for GRh3 (Wu et al., 2023). Luteolin experiments confirmed that it inhibits the proliferation of colon cancer cells through the pyroptosis pathway. Luteolin treatment increased the expression of Caspase1 and Gasdermin D. And we observed through immunofluorescence co-localization that NLRP3/Gasdermin D combined and inhibited CRC (Chen et al., 2022).

Additionally, the component of TCM was related to the tumor microenvironment. Ginsenoside R1 significantly decreased intestinal inflammatory factors TNF-a, IL-6, IL-1β, and IL-22. It also altered the composition of gut microbiota, effectively alleviating chronic inflammation and repairing the intestinal microenvironment in the AOM/DSS model (Wang et al., 2023). Baicalin could prompt apoptosis in both HCT116 and CT-26 by activating the TLR4/NF-kB pathway, significantly reducing the proliferation of colon cancer cells. Alongside this, baicalin could improve the anti-tumor immune function, down-regulating PD-L1 expression and upregulating the CD4⁺ and CD8⁺ T cell ratio, thereby improving the tumor immune microenvironmen (Yang et al., 2020). What’s more, it has been reported that using Emodin on the AOM/DSS mouse model decreased inflammatory cell infiltration and pro-inflammatory enzyme expression in the tumor microenvironment while increasing CD3 (+) T-lymphocyte levels. Moreover, it effectively reduced the cell viability of SW620 and HCT116 cells in in vitro experiments (Zhang Y et al., 2021).