Mechanisms and benefits of phytochemicals as an alternative therapeutic strategy in female cancers.

Breast cancer remained the most prevalent type of cancer detected among women in 2020, constituting a significant portion of all reported cases of female cancer, approximately one-fourth ( Arnold et al., 2022 ). The incidence and mortality rates of breast cancer continue to rise in both developing and developed countries ( Li et al., 2019 ). Numerous risk factors contribute to this trend, with epidemiological data indicating that the incidence of breast cancer is primarily associated with sex, age, economic development, hormonal status, estrogen levels, genetic factors, breast changes, ionizing radiation, diet, obesity, smoking, and nicotinism ( Smolarz, Nowak, & Romanowicz, 2022 ). The World Health Organization (WHO) recognizes at least 18 different histological types of breast cancer, with triple-negative breast cancer comprising 15%−20% of all cases ( Łukasiewicz et al., 2021 , Smolarz et al., 2022 ). The survival rates and prognosis of treated breast cancer have shown significant improvement over time. However, it is important to acknowledge that traditional therapies still face certain limitations and challenges, such as breast cancer’s multi-drug resistance to chemotherapy drugs. A significant amount of phytochemicals found in fruits and vegetables can have a positive impact on breast cancer treatment by regulating various signaling pathways, inhibiting angiogenesis, and inducing apoptosis ( Grosso et al., 2017 ). In recent times, phytochemicals have emerged as valuable natural dietary ingredients in the prevention and treatment of breast cancer ( Fig. 1 ) ( Nardin et al., 2020 , Singh et al., 2020 , Waks and Winer, 2019 ). Fig. 1 Phytochemicals prevent and treat breast cancer. (1) Ursolic acid can induce S-phase arrest in breast cancer cells and inhibit cell proliferation. (2) Fisetin can induce expression of HO-1, and then reduce expression levels of MMP-2 and MMP-9 in breast cancer cells, and reduce invasion and metastasis of breast cancer cells. (3) Honokiol can inhibit glycolysis of breast cancer cells by regulating expression of HIF-1 α . (4) Black cohosh plays an anti-estrogen role, inhibits E2, and has a good inhibitory effect on proliferation of breast tissue. (5) Cyanidin-3- O -glucoside can inhibit the phosphorylation of EGFR and AKT, and promote degradation of EGFR and activation of Caspase-3, 9, leading to apoptosis of cancer cells. Phytochemicals prevent and treat breast cancer. (1) Ursolic acid can induce S-phase arrest in breast cancer cells and inhibit cell proliferation. (2) Fisetin can induce expression of HO-1, and then reduce expression levels of MMP-2 and MMP-9 in breast cancer cells, and reduce invasion and metastasis of breast cancer cells. (3) Honokiol can inhibit glycolysis of breast cancer cells by regulating expression of HIF-1 α . (4) Black cohosh plays an anti-estrogen role, inhibits E2, and has a good inhibitory effect on proliferation of breast tissue. (5) Cyanidin-3- O -glucoside can inhibit the phosphorylation of EGFR and AKT, and promote degradation of EGFR and activation of Caspase-3, 9, leading to apoptosis of cancer cells. Ursolic acid (UA) is a pentacyclic triterpenoid compound found in natural plants like Prunella vulgaris L. It exhibits pharmacological properties including liver protection, wound healing, antibacterial, anti-inflammatory, and antiviral effects ( Li et al., 2019 , Mlala et al., 2019 ). Extensive in vitro and in vivo experiments have demonstrated the significant potential of UA in combating breast cancer through mechanisms such as apoptosis induction, cell cycle arrest, angiogenesis inhibition, and metastasis suppression ( Iqbal et al., 2018 ). Wang et al. conducted experiments that revealed the ability of a specific concentration of UA to induce S-phase arrest in breast cancer cells and inhibit cell proliferation. Furthermore, UA up-regulated the levels of pro-apoptotic proteins B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) and cleaved Poly ADP-ribose polymerase (PARP) while down-regulating the level of anti-apoptotic protein Bcl-2, thereby facilitating mitochondria-mediated apoptosis of breast cancer cells. Interestingly, the researchers proposed that UA could impede glycolytic metabolism and mitochondrial respiratory function, effectively inhibiting breast cancer growth and metastasis. The results showed that UA may increase the transcriptional activity of the caveolin-1 (Cav-1) gene by activating the transcription factor SP1 signaling pathway, and the overexpression of Cav-1 can inhibit the glycolytic metabolism of breast cancer. This suggests that UA can impede the progression of breast cancer cells by activating the SP1/Cav-1 pathway to impair glycolysis metabolism ( Wang et al., 2021 ). Another experimental study reported that UA’s ability to reduce the expression of the tumor promoter nuclear factor erythroid 2-related factor 2 (Nrf2) in MDA-MB-231 breast cancer cells through the kelch-like ECH-associated protein 1 (Keap1)/Nrf2 pathway and epidermal growth factor receptor (EGFR)/Nrf2 pathway, thereby suppressing cancer cell proliferation ( Zhang, Li, Gong, & Liu, 2020 ). UA is considered safe with low toxicity and shows promise as a potential phytochemical for breast cancer treatment. Fisetin, a bioactive flavonoid, is present in Anacardiaceae plants ( Rhus succedanea L.). It has been found to possess various beneficial properties such as antioxidant, anti-inflammatory, anti-angiogenic, neuroprotective, and anti-tumor activities ( Kashyap et al., 2018 , Sundarraj et al., 2018 ). Fisetin effectively suppressed the growth of 4 T1 cells in a concentration-dependent manner. At a concentration of 40 µmol/L, fisetin primarily induced early apoptosis, whereas at 80 µmol/L, it mainly induced late apoptosis. The underlying mechanism involved the down-regulation of p-PI3K, p-Akt, p-mTOR, and the anti-apoptotic protein Bcl in 4 T1 cells. Additionally, fisetin up-regulated the expression of the pro-apoptotic protein Bax, which inhibited the PI3K/Akt/mTOR signaling pathway. Consequently, this inhibition resulted in the suppression of migration and invasion abilities of 4 T1 cells and the induction of apoptosis ( Sun et al., 2018 ). In addition, fisetin has the ability to increase Nrf2 protein expression in the nucleus. This leads to an increase in the expression of various oxidases, including HO-1. As a result, enzyme activities and mRNA expression levels of MMP-2 and MMP-9 are reduced in breast cancer 4 T1 and JC cells. MMP-2 and MMP-9 are important members of the MMPs family, which are closely associated with the invasion and metastasis of breast cancer. The decrease in MMP-2 and MMP-9 expression weakens the motility of cells, effectively reducing the invasion and metastasis of breast cancer cells. However, the role of HO-1 in tumors is a subject of controversy and further experimental studies are required to understand its mechanism of action ( Tsai et al., 2018 ). In conclusion, fisetin shows promise as a natural drug for the prevention and treatment of breast cancer. Honokiol, a bisphenol phytochemical found in Houpoea officinalis , is traditionally used for treating conditions such as headache, anxiety, stroke, and constipation. It exhibits several beneficial properties, including antioxidant, anti-inflammatory, anti-arrhythmic, anti-angiogenic, and anti-cancer activities. Regarding its anti-tumor effects, honokiol has been shown to regulate multiple molecular targets and effectively inhibit cancer progression ( Miao et al., 2023 , Ong et al., 2019 ). A study by Yi et al. demonstrated that honokiol can suppress the growth of breast cancer cells both in vitro and in vivo by inhibiting glycolysis. The underlying mechanism involves the regulation of hypoxia-inducible factor 1 α (HIF-1 α ) expression, leading to increased oxygen consumption rate (OCR), decreased extracellular acidification rate (ECAR), reduced glucose uptake, lactate production, and adenosine triphosphate (ATP) generation in breast cancer cells. Notably, honokiol achieves inhibition of breast cancer cell growth by facilitating the binding of ubiquitin-fold modifier1-specific ligase 1 (UFL1) and BRadiated and E3 ligase 1B (BRE1B) to HIF-1 α , thereby promoting its ubiquitination and subsequent degradation ( Yi, Qi, Huang, Zhou, & Xiong, 2022 ). Earlier experiments have reported that honokiol can regulate the over-transcription factor Nuclear factor kappa-B (NF- κ B) level by reducing the level of endogenous NO produced by breast cancer cells. This, in turn, down-regulates the expression of cyclooxygenase-2 (COX-2) and inhibits the migration of breast cancer cells ( Singh & Katiyar, 2011 ). Wang et al. suggested that honokiol may also inhibit the translation of Snail and Slug genes at the mRNA level. This mechanism targets the reduction of vimentin expression and enhances the increase of E-cadherin expression, thereby preventing the progression of epithelial-mesenchymal transition (EMT) and inhibiting the migration and invasion of breast cancer cells ( Wang, Shang, Li, & Chen, 2019 ). These experimental results suggest that honokiol has the potential to be developed as a novel natural plant compound for inhibiting the growth and metastasis of breast cancer. Cyanidin-3- O -glucoside, a major anthocyanin, is naturally found in Haskap ( Lonicera caerulea L.) berries. This compound possesses several beneficial properties such as anti-inflammatory, anti-cancer, anti-diabetic, anti-toxic, cardiovascular, and neuroprotective effects. In vitro studies have demonstrated its inhibitory effects on different types of cancer cells ( Liang et al., 2021 , Pace et al., 2018 ). Cyanidin-3- O -glucoside can directly bind to the highly expressed ERα36 receptor in MDA-MB-231 cells, leading to the inhibition of downstream signaling pathways. This includes reducing the phosphorylation levels of EGFR and AKT induced by estradiol (E2) and promoting the degradation of EGFR through the proteasome system. As a result, the activation of Caspase-9 and Caspase-3 occurs, ultimately promoting cancer cell apoptosis ( Wang et al., 2016 ). Additionally, cyanidin-3- O -glucoside can effectively inhibit EMT, migration, and invasion of breast cancer cells (MDA-MB-231 and MDA-MB-468). The underlying mechanism involves the upregulation of E-cadherin expression and the downregulation of N-cadherin and vimentin expression in cancer cells treated with cyanidin-3- O -glucoside. Previous studies have demonstrated a positive correlation between E-cadherin expression and krüppel-like factor 4 (KLF4) protein expression. Further investigations revealed that cyanidin-3- O -glucoside suppresses cancer cell invasion and metastasis by reducing the expression of F-box protein 32 (FBXO32), thereby increasing the levels of KLF4 protein ( Chen et al., 2020 ). These studies offer novel insights into the mechanisms through which natural compounds in plants may exert potential preventive or therapeutic effects in treating breast cancer. Black cohosh ( Cimicifuga racemosa L.) is a traditional Chinese medicine. Its roots and rhizome have been historically utilized in the treatment of rheumatic diseases, malaria, sore throat, wind-cold, and childbirth-related complications. Presently, it is globally recognized for its effectiveness in alleviating menopausal symptoms ( Mohapatra et al., 2022 , Szmyd et al., 2018 ). The experiment discovered that black cohosh can decrease the viability of breast cancer cells and reduce the expression of estrogen receptor alpha (ER- α ) and breast cancer susceptibility gene 1 ( BRCA1 ) in a concentration-dependent manner. Other research has indicated that ER- α and BRCA1 may transmit signals through a crosstalk mechanism, potentially promoting the development and growth of breast tumors in the presence of steroid hormones like estrogen. However, black cohosh acts as an anti-estrogen agent and inhibits the proliferation of E2, thereby effectively suppressing the growth of breast tissue ( Crone et al., 2019 ). Poschner’s experiments revealed that black cohosh had the potential to stimulate androgen production by suppressing the expression of sulfotransferase family 2A member 1 (SULT2A1). This enzyme is responsible for converting dehydroepiandrosterone (DHEA) to dehydroepiandrosterone sulfate (DHEA-S) in breast cancer MCF-7 cells. By inhibiting DHEA sulfation, black cohosh reduces the activity of SULT2A1, leading to an increase in androgen levels (AD and T), without affecting estrogen levels. It is important to note that black cohosh is considered safe and does not promote tumor progression in hormone-dependent breast cancer patients ( Poschner et al., 2020 ). Therefore, black cohosh has demonstrated significant benefits for women’s health and holds the potential for developing novel strategies in breast cancer treatment. Berberine combined with emodin can inhibit the growth of breast cancer cells and promote cell apoptosis by inhibiting the inactivation of mTOR and Akt signaling pathways induced by salt-inducible kinase 3 (SIK3) ( Ponnusamy, Kothandan, & Manoharan, 2020 ). Solasonine has the ability to trigger the mitochondrial cytochrome C -dependent apoptosis pathway, which can effectively hinder the progression of breast cancer Bcap-37 cells ( Li et al., 2016 ). Sesamin attenuates cancer cell survival by inhibiting AKT, NF- κ B, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in MDA-MB231 cells, leading to the down-regulation of programmed death ligand 1 (PD-L1) expression. In addition, sesamin could effectively reduce the migration ability of breast cancer cells by inhibiting the expression of MMP-9 and MMP-2 ( Kongtawelert, Wudtiwai, Shwe, Pothacharoen, & Phitak, 2020 ).

Yufan Zhao: Writing – original draft, Writing – review & editing. Shimenghui Deng: Writing – review & editing, Visualization. Danli Cao: Writing – review & editing, Supervision. Caiji Lin: Writing – review & editing. Mengzhi Xu: Writing – review & editing. Jiaxing Wang: Writing – review & editing. Lingjie Luo: Writing – review & editing. Shulin Liu: Writing – review & editing, Funding acquisition, Supervision. Huidi Liu: Writing – review & editing, Funding acquisition, Supervision.

Ovarian cancer, known for its high mortality rate among gynecologic malignancies, is responsible for 239 000 new cases and 152 000 deaths globally each year. Epithelial ovarian cancer is the most prevalent type, accounting for 90% of cases across all races and ethnic groups ( Menon, Karpinskyj, & Gentry-Maharaj, 2018 ). Risk factors for ovarian cancer include smoking, hormonal replacement therapy, dietary factors, BRCA1 mutation carrier, BRCA2 mutation carrier, family history, Lynch syndrome, uninterrupted ovulation cycles, endometriosis, and ethnicity/race. A strong risk factor for ovarian cancer is having a history of breast cancer or a family history of ovarian cancer ( Menon et al., 2018 , Stewart et al., 2019 , Torre et al., 2018 ). The origin of ovarian cancer is still uncertain and is believed to be influenced by other gynecological tissues ( Moffitt, Karimnia, Stephens, & Bilandzic, 2019 ). Referred to as the ‘silent killer’, ovarian cancer poses challenges in terms of treatment and cure due to its nonspecific symptoms, often leading to late-stage diagnosis ( Stewart, Ralyea, & Lockwood, 2019 ). The current treatment approach involves a combination of platinum and taxane chemotherapy following surgery. However, this treatment is hindered by severe side effects and drug resistance, particularly with cisplatin ( Pistollato et al., 2017 ). Consequently, there is a pressing need for more effective and well-tolerated treatment regimens. Phytochemicals have shown promise in inhibiting tumor cell growth, promoting autophagy, triggering apoptosis, and targeting ovarian cancer stem cells (CSCs) specifically ( Fig. 4 ) ( Pistollato et al., 2017 ). Fig. 4 Phytochemical effects on changes of genes or molecules in ovarian cancer cells, among which naringenin can improve gut microbiota, thereby inhibiting progression of ovarian cancer. Phytochemical effects on changes of genes or molecules in ovarian cancer cells, among which naringenin can improve gut microbiota, thereby inhibiting progression of ovarian cancer. Naringenin is a flavonoid compound primarily sourced from Anacardium occidentale L. and commonly found in a range of Citrus fruits. It has been found to possess various biological activities, including antioxidant, anti-tumor, antiviral, anti-inflammatory, neuroprotective, and liver-protective effects. Studies conducted in vitro and in vivo have demonstrated that naringenin inhibits cancer progression through multiple mechanisms, such as suppressing cell proliferation, inducing apoptosis, inhibiting cell invasion and metastasis, and modulating signaling pathways ( Motallebi et al., 2022 , Salehi et al., 2019 ). Our laboratory has specifically observed that naringenin can effectively inhibit the occurrence and progression of epithelial ovarian cancer by targeting the EGFR/PI3K/Cyclin D1 (CCND1) pathway. Furthermore, naringenin has shown the ability to improve the gut microbiota and alleviate epithelial ovarian cancer in vivo . Naringenin not only directly inhibited cell proliferation in vitro but also repressed the growth of epithelial ovarian cancer in vivo , with the oral route showing greater effectiveness than parenteral administration. Importantly, no adverse side effects of naringenin have been observed in either in vivo or in vitro experiments, which aligns with its natural occurrence in dietary plants ( Lin et al., 2022 ). Let’s expand on the gut microbiota mentioned here. The gut microbiota can convert plant lignans found in human food into mammalian lignan enterolactone (ENL), which, when administered in high doses, exhibits significant inhibition of ovarian malignant tumor proliferation, invasion, and metastasis with minimal side effects ( Liu et al., 2017 , Zeng et al., 2023 ). In the future, it would be worthwhile to explore the impact of plant compounds that can modulate gut microbiota on cancer immune responses and immunotherapy. By combining phytochemicals, gut microbiota, and traditional therapies, novel treatment strategies can be developed to enhance anti-cancer efficacy and reduce toxicity ( Fig. 5 ) ( Vivarelli et al., 2019 , Zhou et al., 2021 ). Fig. 5 Gut microbiota can convert plant lignans in human food into mammalian lignan enterolactone (ENL) and inhibit cancer progression. Gut microbiota can convert plant lignans in human food into mammalian lignan enterolactone (ENL) and inhibit cancer progression. Mangiferin, a natural active compound found in higher plants and mango ( Mangifera indica L.) fruits, possesses antiviral, antioxidant, anti-inflammatory, and anti-cancer properties. Studies have shown that mangiferin can reduce the inflammatory response in various organs, thereby preventing tumor formation ( Hu et al., 2023 , Mei et al., 2021 ). Zou et al. investigated the effects of mangiferin on ovarian cancer cells and discovered that it induced apoptosis through the caspase pathway, as evidenced by the activation of Caspase-3 and Caspase-9. Interestingly, mangiferin also led to a significant decrease in the expression of Notch, highlighting the important role of Notch in mangiferin-mediated apoptosis. Overexpression of Notch3 was found to hinder cell apoptosis, but mangiferin was able to reverse this process by inhibiting Notch3 levels, resulting in the inhibition of ovarian cancer cells ( Zou et al., 2017 ). Further research in our laboratory revealed that high doses (60 mg/kg) of mangiferin had a more pronounced effect on inhibiting tumor growth. Additionally, mangiferin was observed to significantly inhibit the proliferation and migration of epithelial ovarian cancer cells by down-regulating the expression of MMP-2 and MMP-9. Importantly, no side effects were detected during the experiment ( Zeng et al., 2020 ). These findings suggest that mangiferin could serve as a promising targeted treatment for ovarian cancer, warranting further investigation into its mechanism of action. Osthole, a natural coumarin extracted from Cnidium monnieri (L.) Cuss., is a traditional Chinese medicine with a wide range of pharmacological activities. It has been found to exhibit anti-cancer, anti-inflammatory, anti-oxidation, anti-osteoporosis, antibacterial, and antiviral properties. Osthole is considered safe with minimal toxic and side effects, making it valuable for further development and utilization ( Bae et al., 2021 , Yang et al., 2022 ). Osthole can inhibit the progression from G2 to M phase in ovarian cancer cells. This was achieved by reducing the levels of Cyclin B1 and Cdc2, while increasing the phosphorylation of Tyr-15 at the inhibitory site of Cdc2. Osthole also demonstrated significant induction of apoptosis through the mitochondrial pathway. This was evidenced by an increase in the Bax/Bcl-2 ratio and activation of Caspase-3 and Caspase-9. Furthermore, the osthole exhibited effective inhibition of ovarian cancer invasion and metastasis by suppressing the expression of MMP-2 and MMP-9 ( Jiang et al., 2016 ). Additionally, osthole can induce autophagy and pyroptosis in ovarian cancer cells. The expression level of LC3-II in ovarian cancer cells treated with osthole was increased, triggering LC3-mediated autophagy in ovarian cancer cells. C-terminal fragment of Gasdermin E (c-GSDME) plays an important role in pyroptosis. Osthole can induce the expression of c-GSDME, which leads to pyroptosis in ovarian cancer cells ( Liang et al., 2020 ). Osthole shows promise as a potential drug for the treatment of ovarian cancer. It can be considered for clinical use in combination with other drugs to treat patients. Nobiletin, a compound found in Citrus fruit peels, has been identified as a promoter of carbohydrate metabolism with various beneficial effects such as anti-inflammatory, anti-tumor, anti-atherosclerosis, and anti-aging properties. Currently, researchers are investigating the potential effects of nobiletin on different types of cancers including breast, ovarian, gastric, lung, and liver cancers ( Goh et al., 2019 , Yang et al., 2020 ). In a study conducted by Jiang et al., it was demonstrated that nobiletin can induce G0/G1 cell cycle arrest, effectively inhibiting the proliferation of drug-resistant ovarian cancer cells. This mechanism is believed to be achieved through the enhancement of p53 and p21 expression. Furthermore, the overexpression of AKT was found to be involved in the autophagy degradation of SKOV3/TAX cells induced by nobiletin. AKT plays a role in regulating the degradation of cathepsin B (CTSB), a crucial lysosomal protease involved in autophagic degradation. Nobiletin was found to significantly reduce the expression of CTSB, leading to the inhibition of autophagic flux and the promotion of cell apoptosis ( Jiang, Guo, & Wang, 2018 ). However, Zhang’s experimental study was not consistent with the conclusion of Jiang et al., who found that nobiletin could induce autophagy in human ovarian cancer cells, possibly by using different cell lines. In the study, nobiletin was observed to induce ROS production and reduce mitochondrial membrane potential in ovarian cancer HOCC cells (A2780 and OVCAR3), ultimately leading to cell death. Additionally, nobiletin was found to regulate autophagy, promoting GSDMD/GSDME-mediated pyroptosis and inhibiting the development of cancer cells ( Zhang et al., 2020 ). Nobiletin is anticipated to emerge as a potential natural drug for ovarian cancer treatment. However, it is important to note that certain studies in this regard are still in their early stages and require further development and validation. Betulinic acid (BA) is a lupane-type pentacyclic triterpenoid compound that occurs naturally and can be extracted from birch tree bark. BA and its derivatives have been found to possess various biological activities including anti-tumor, anti-inflammatory, anti-HIV, anti-malarial, antibacterial, and antioxidant effects ( An et al., 2020 , Jiang et al., 2021 ). BA inhibited the proliferation of A2780 human ovarian cancer cells in a concentration-dependent manner. The apoptotic mechanism of BA involves up-regulation of cleaved Caspase-8, −9, −3, and Bax expression, as well as down-regulation of Bcl-2 expression through both mitochondrial-dependent and independent pathways ( Lee et al., 2019 ). Additionally, BA not only induced apoptosis in cancer cells but also hindered their migration in an ovarian cancer mouse model. The experimental findings exhibited alterations in metastatic proteins associated with the EMT process. Specifically, the expression of N-cadherin was down-regulated, while the expression of E-cadherin was up-regulated. These changes indicated the inhibition of cell invasion and metastasis ( Liao, Liu, Xie, & Zhou, 2020 ). Moreover, Jin et al. identified a potential synergistic effect of BA when combined with doxorubicin (DOX), an anti-tumor drug. This combination exhibited enhanced treatment efficacy and reduced cardiac toxicity in ovarian cancer patients ( Jin, Zhou, Zhang, & Lv 2019 ). The research prospects of BA in the development of anti-ovarian cancer drugs are broad. Ethanol extract of Amomum tsaoko (At-EE) inhibits the induction of angiogenesis by ovarian cancer cells by activating endoplasmic reticulum stress and inhibiting the feedback loop of phosphorylated transducer and activator of transcription-3 (p-STAT3), NF- κ B and vascular endothelial growth factor (VEGF)/IL-6 ( Chen et al., 2020 ). Puerarin can inhibit the progression of ovarian cancer cells by regulating intestinal microbiota and promoting the expression of tumor suppressor genes ( Ye, Gao, Fang, Xu, & He, 2022 ). Gentisyl alcohol can inhibit the growth of ovarian cancer epithelial cells through MAPK and PI3K/AKT pathways ( Ham et al., 2019 ).

Cervical cancer is a prevalent malignant tumor among women, ranking second only to breast cancer in terms of incidence. Approximately 12% of women worldwide are infected with human papillomavirus (HPV), which is the leading cause of cervical cancer ( Sousa Morais et al., 2020 ). HPV is a small non-enveloped DNA virus with 80 well-classified types. Among these types, high-risk HPV 16 and HPV 18 are highly associated with 70% of cervical cancers. Additionally, the oncoproteins E5, E6, and E7 play crucial roles in the progression of cervical cancer cells ( Ramakrishnan, Partricia, & Mathan, 2015 ). Factors that increase the risk of cervical cancer include early age of first sexual intercourse, having multiple sexual partners, smoking, co-infections, prolonged use of oral contraception, and cervix dysplasia ( Johnson, James, Marzan, & Armaos, 2019 ). The occurrence of cervical cancer is a complex process, and the clinical treatment options mainly consist of surgery, radiotherapy, and chemotherapy. However, extensive experimental results and clinical practices have confirmed that surgery and radiotherapy alone cannot completely control and eliminate the occurrence and metastasis of cervical cancer. Therefore, despite the availability of various prevention and treatment methods for cervical cancer, such as HPV screening, prophylactic HPV vaccines, surgery, radiotherapy, and chemotherapy, the global burden of this disease remains substantial ( Wang et al., 2020 ). Nowadays, a large number of scientific studies have reported that plants can be used as natural sources for cervical cancer treatment, as an alternative to drugs that have shown some harmful side effects in humans ( Fig. 2 ) ( Wang et al., 2013 ). They can inhibit the proliferation of HPV cells by inducing apoptosis, growth arrest, and regulating signal transduction pathways ( Moga et al., 2016 ). Fig. 2 Part of the mechanism of phytochemicals in cervical cancer is shown. Part of the mechanism of phytochemicals in cervical cancer is shown. Apigenin, a natural flavonoid, is primarily sourced from plants in the Asteraceae family, including those in the Artemisia , Achillea , Matricaria , and Tanacetum genera. It exhibits various biological activities, such as cardiovascular and cerebrovascular protection, as well as antiviral and antibacterial properties. Numerous experimental studies have reported that apigenin possesses potent anticancer properties against various types of cancer. This is mainly attributed to its strong antioxidant and anti-inflammatory activities ( Imran et al., 2020 , Liu et al., 2020 , Salehi et al., 2019 ). Yang et al. demonstrated that the expression of Bax increased and the expression of Bcl-2 decreased in Hela cells treated with apigenin, leading to an increased proportion of apoptotic cancer cells. Moreover, apigenin concentration-dependently inhibited the rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase (MEK)/ERK signaling pathway by down-regulating the expression of p-MEK and p-ERK, thereby suppressing the proliferation of cancer cells ( Yang, Fa, & Li, 2018 ). Zhang et al. investigated the effects of apigenin on estrogen receptor signaling and expression induced by histamine in HeLa cells. They found that apigenin attenuated the abnormal estrogen receptor signaling, inhibiting cell proliferation both in vitro and in vivo . The study also revealed that apigenin inhibited the PI3K/Akt/mTOR signaling pathway by modulating abnormal estrogen receptor expression, leading to apoptosis and autophagy of HeLa cells ( Zhang et al., 2020 ). Chen et al. provided further insights into the molecular mechanism of apigenin in treating cervical cancer. The study findings revealed a noteworthy decrease in the expression of N-cadherin, fibronectin, and vimentin in cervical cancer cells treated with apigenin. In contrast, the expression of laminin and E-cadherin showed an increase, indicating a reduction in the EMT process and an inhibition in the invasion and metastasis of cancer cells ( Chen et al., 2022 ). In summary, apigenin is a promising plant compound with the potential as an anti-cervical cancer therapeutic. It holds promise for development into a clinical drug. α -Mangostin, a phytochemical extracted from the peel of Mangosteen fruit, has demonstrated significant biological activity in terms of antiviral, antioxidant, and anti-tumor effects. Several studies have reported its potent anticancer activity against various cancer cells ( Chen et al., 2018 , Chien et al., 2020 ). In a study, it is observed that α -mangostin inhibits cancer cell proliferation and immortalization by down-regulating HPV E6/E7 gene expression. Additionally, it induces the production of vimentin, a factor that effectively hinders the initial steps of HPV16 infection. Moreover, α -mangostin inhibits the expression of voltage-gated potassium channel KCNH1, resulting in cell cycle arrest at the G1 phase and subsequent cervical cancer cell arrest ( Díaz et al., 2023 ). Another study reveals that α -mangostin activates the apoptosis signal-regulating kinase (ASK)/p38 mitogen-activated protein kinase (p38) signaling pathway by increasing the production of reactive oxygen species (ROS), leading to mitochondrial rupture and loss of matrix metalloproteinase (MMP). This process triggers the release of pro-apoptotic proteins Bax and cytochrome C (Cyto C) while decreasing the release of anti-apoptotic protein Bcl-2. Consequently, the Caspase-9/Caspase-3 cascade is activated, inducing apoptotic cell death in SiHa cells ( Lee et al., 2017 ). These experimental studies offer new insights and demonstrate the potential value of α -mangostin in the prevention and treatment of cervical cancer. Silibinin, a polyphenolic flavonoid lignan isolated from milk thistle [ Silybum marianum (L.) Gaertn.], is highly effective in protecting the liver. Numerous in vitro and in vivo studies have confirmed its anti-cancer properties, including the inhibition of cell proliferation, induction of cell apoptosis, modulation of various signal transduction pathways, and suppression of angiogenesis and metastasis ( Jahanafrooz et al., 2018 , Tuli et al., 2021 ). A previous study reported that silibinin can inhibit cancer cell growth by reducing the protein levels of cyclin-dependent kinase 1 (CDK1) and CDK2 in Hela cells. Moreover, it was observed that silibinin down-regulated Bcl-2 protein expression, leading to the release of Cyto C from mitochondria into the cytoplasm and the activation of Caspase-9. Additionally, the up-regulation of Fas and FasL expression and the activation of Caspase-8 were observed, which further promoted cancer cell apoptosis ( Jahanafrooz, Motamed, Rinner, Mokhtarzadeh, & Baradaran, 2018 ). To delve deeper into this phenomenon, You et al. demonstrated that silibinin-induced down-regulation of cell division cycle 25C (Cdc25C), CDK1, and Cyclin B1 in cervical cancer cells resulted in cell cycle arrest at the G2/M phase and inhibited cell proliferation. This effect may be attributed to the increased expression of Drp1, a protein critical for mitochondrial fragmentation and G2/M cell cycle arrest in cervical cancer cells ( You et al., 2020 ). These experimental studies collectively contribute to establishing a theoretical foundation for utilizing silibinin as a natural plant medicine in the treatment and prevention of cervical cancer. Baicalein is the most abundant flavonoid compound found in Scutellaria baicalensis Georgi. It possesses a range of biological effects, including antioxidant, antiviral, anti-inflammatory, anti-angiogenesis, and anti-cancer properties. Baicalein has been known for its anti-cancer properties for some time, primarily by inhibiting various biological processes such as cell proliferation, metastasis, angiogenesis, and promoting apoptosis and autophagy in cancer cells ( Morshed et al., 2023 , Tuli et al., 2020 ). Baicalein can arrest the cell cycle at the G0/G1 phase and prevent the transition to the S phase by inhibiting the expression of Cyclin D1 in SiHa cells and HeLa cells. This process is mediated by the AKT/glycogen synthase kinase 3 beta (GSK3 β) /Cyclin D1 pathway. Baicalein reduces the expression of p-GSK3 β by inhibiting the protein level of p-AKT in cancer cells, thereby enhancing GSK3 β activity and enabling GSK3 β to phosphorylate and degrade Cyclin D1 ( Wu, Yang, Dang, Peng, & Dai, 2018 ). In the experiments conducted by Yu et al. to investigate the impact of baicalein on cervical cancer cell apoptosis, it was observed that the levels of Bax and Caspase-3 increased, while the levels of Bcl-2 decreased in C33A cells treated with baicalein. This indicated the promotion of cancer cell apoptosis. Further studies revealed that baicalein down-regulated the expression of COX-2, interleukin-8 (IL-8), tumor necrosis factors (TNF), FLICE-like inhibitory protein (FLIP), and X-linked inhibitor of apoptosis protein (XIAP), which are regulated by the NF- κ B signaling pathway. These findings suggest that baicalein may inhibit cancer cell proliferation and promote cell apoptosis by inhibiting the activity of the NF- κ B signaling pathway ( Yu et al., 2018 ). Baicalein exhibits significant potential for research in the prevention and treatment of cervical cancer. Tanshinones are terpenoids extracted from the root of Salvia miltiorrhiza Bunge, a traditional Chinese medicine, known for their traditional functions of promoting blood circulation and removing blood stasis. Within this compound family, tanshinone I, tanshinone IIA, tanshinone IIB, crypto tanshinone, and others have shown significant potential in fighting cancer. Previous studies have demonstrated their effectiveness in inhibiting gynecological tumors both in vivo and in vitro through various molecular mechanisms ( Zhou et al., 2022 , Zhan et al., 2023 ). Upon treatment of SiHa cells with tanshinone IIA, a notable decrease was observed in the expression levels of oncogene E6 and E7 mRNA and protein. Additionally, the study found increased expression of Bax and decreased expression of Bcl-2, promoting apoptosis of cancer cells. Furthermore, tanshinone IIA was found to inhibit glucose uptake and extracellular lactate production in SiHa cells. This inhibition is attributed to the reduction in phosphorylation levels of Akt and mTOR, leading to decreased expression of HIF-1 α and subsequent inhibition of cancer cell glycolysis ( Liu et al., 2019 ). After the administration of tanshinone IIA in Hela cells, the results showed an increase in the levels of gasdermin D (GSDMD) and Caspase-1 activity. It was observed that Caspase1 directly cleaved GSDMD as well as the precursor cytokines pro-IL-1 β and pro-IL-18. This led to an upregulation of IL-1 β and IL-18 expression, ultimately promoting cancer cell pyroptosis. Furthermore, the study also revealed an elevated level of miR-145, when overexpressed, which demonstrated inhibitory effects on cancer cell proliferation, invasion, and metastasis ( Tong, Guo, & Yang, 2020 ). Tanshinone IIA, as a natural product, is increasingly being recognized for its potential in cancer prevention and treatment, particularly in the case of cervical cancer. It holds promising therapeutic prospects. Pomegranate peel polyphenols, alone or in combination, could inhibit cervical cancer cell growth by inducing apoptosis, cell cycle arrest, inhibiting DNA synthesis, and regulating different signaling pathways ( Teniente et al., 2023 ). Curcumin can reduce the migration of cervical cancer cells by reducing the expression level of Pirin, thereby inhibiting EMT ( Aedo-Aguilera et al., 2019 ). Luteolin combined with asiatic acid produced anticancer effects on cervical cancer cells. Its mechanism is to down-regulate the PI3K/ AKT, JNK/p38 MAPK, and FAK signaling pathways and up-regulate the ERK signaling pathway, thereby inducing cell apoptosis and inhibiting cancer cell migration ( Chen, Wu, Yang, & Hsiao, 2023 ).

This review focuses on the mechanisms of action of certain phytochemicals on female cancer cells and emphasizes the importance of exploring these natural resources to investigate their effects. Although the development of cancer cells is a complex process influenced by various factors, phytochemicals, as natural products, possess unique molecular structures. These compounds can have similar or distinct mechanisms of action, including cell cycle arrest, promotion of endogenous and exogenous apoptosis, and inhibition of the EMT process. Depending on their specific mechanisms, they can be used individually or in combination. For instance, a combination of three phytochemicals, namely piperine, sulforaphane, and thymoquinone, is used alongside conventional therapies to reduce drug resistance in breast cancer ( Aumeeruddy & Mahomoodally, 2019 ). Furthermore, these compounds can serve as points of reference for each other, to investigate their potential to inhibit cancer cell development through alternative pathways or affect other types of cancer ( Table 2 ). Resveratrol, as traditional medicine, has shown promising effects in the treatment of breast cancer, cervical cancer, ovarian cancer, and other female cancers ( Rauf et al., 2018 ). However, it is worth noting that phytochemicals used in endometrial and ovarian cancers are not as abundant as those used in breast and cervical cancers. Further research is needed to determine if the developed phytochemicals can have an impact on other types of cancer, which requires systematic studies. Table 2 Classification and research status of phytochemicals. Structural types Phytochemicals Cancer treatment Research status Terpenoids Pentacyclic triterpenoid Ursolic acid Breast cancer Inhibit cancer cells proliferation promote cancer cells apoptosis inhibit cancer cells metastasis Betulinic acid Ovarian cancer Promote cancer cells apoptosis suppress cancer cells migration Triterpene saponin Black cohosh Breast cancer Inhibit cancer cells growth Diterpenoid Tanshinone IIA Cervical cancer Promote cancer cells apoptosis promote cancer cells pyroptosis Flavonoids Fisetin Breast cancer Promote cancer cells apoptosis suppress cancer cells migration and invasion Cyanidin-3- O -glucoside Breast cancer Promote cancer cells apoptosis suppress cancer cells migration and invasion Apigenin Cervical cancer Inhibit cancer cells proliferation promote cancer cells apoptosis and autophagy suppress cancer cells migration and invasion Silibinin Cervical cancer Inhibit cancer cells growth promote cancer cells apoptosis inhibit cancer cells proliferation Baicalein Cervical cancer Inhibit cancer cells proliferation promote cancer cells apoptosis Genistein Endometrial cancer Inhibit cancer cells proliferation promote cancer cells apoptosis Kaempferol Endometrial cancer Inhibit cancer cells proliferation promote cancer cells apoptosis Naringenin Ovarian cancer Inhibit cancer cells proliferation suppress cancer cells migration and invasion Mangiferin Ovarian cancer Promote cancer cells apoptosis suppress cancer cells migration and invasion Nobiletin Ovarian cancer Inhibit cancer cells proliferation promote cancer cells autophagy and pyroptosis Lignans Honokiol Breast cancer Inhibit cancer cells growth suppress cancer cells migration Saponins Asparanin A Endometrial cancer Inhibit cancer cells proliferation suppress cancer cells migration and invasion Coumarins Osthole Ovarian cancer Promote cancer cells apoptosis suppress cancer cells migration and invasion promote cancer cells autophagy and pyroptosis Quinones Anthrone α -Mangostin Cervical cancer Inhibit cancer cells proliferation promote cancer cells apoptosis Naphthoquinone Juglone Endometrial cancer Inhibit cancer cells proliferation suppress cancer cells migration and invasion Phenols 6-Shogaol Endometrial cancer Inhibit cancer cells proliferation suppress cancer cells migration and invasion Classification and research status of phytochemicals. It is important to recognize that while phytochemicals generally have low toxicity and few side effects, not all phytochemicals are completely non-toxic. The effects of some phytochemicals may vary depending on their concentration in the human body, and excessive or insufficient doses can lead to serious adverse reactions. Therefore, when developing new natural products, it is crucial to carefully control the effective dosage to prevent the occurrence of adverse reactions. Although plant compounds are naturally abundant, they have limited efficacy in the body due to poor water solubility or low concentration. To address this, researchers have developed various technologies to improve the bioavailability of these compounds. One such technology is the use of nanocarriers, which enhance the solubility and stability of phytochemicals, enabling targeted drug delivery ( Chavda et al., 2023 ). In addition, the gut microbiota mentioned in naringenin part also has the potential to enhance the effectiveness of anticancer drugs. Gut microbiota has the ability to interact with drugs that have low bioavailability, converting them into secondary metabolites that have higher bioavailability or activity ( Guo & Wu, 2017 ). This interaction can result in beneficial effects, making gut microbiota a promising target for enhancing the efficacy of tumor treatment while minimizing side effects ( Cheng et al., 2020 , Ma et al., 2019 ). In conclusion, conventional therapies have several limitations in treating cancer, and natural bioactive drugs offer significant potential for cancer prevention and treatment. In the future, multidisciplinary integration can be employed to discover more natural products, allowing researchers to tap into this vast natural resource and develop safer and more effective anticancer drugs. This will lay a solid foundation for utilizing natural drugs in the fight against tumors.

The global incidence of endometrial cancer in 2020 was 417 336 cases, and endometrial cancer is the sixth most common cancer in women ( Makker et al., 2021 ). Especially in industrialized countries, and its incidence has been increasing in recent years, ranking second after cervical cancer. Several factors contribute to a woman’s risk of developing endometrial cancer, including certain medications (such as estrogen and progestins, tamoxifen, and hormonal contraceptives), obesity, diabetes, reproductive factors, and diet and exercise ( Constantine, Kessler, Graham, & Goldstein, 2019 ). Clinically, two clinicopathological variants are recognized: estrogen-related (type I, endometrioid carcinoma) and non-estrogen-related (type II, non-endometrioid carcinoma) ( Matias-Guiu & Prat, 2013 ). Despite significant advancements in our understanding of the biology of endometrial cancer, several treatment aspects remain controversial. These include the role of surgical lymph node evaluation and the selection of patients for adjuvant radiotherapy or chemotherapy ( Brooks et al., 2019 ). Therefore, there is an urgent need to explore new natural compounds as potential therapeutic drugs ( Fig. 3 ). Fig. 3 Changes in genes or molecules within endometrial cancer cells after phytochemical action. Changes in genes or molecules within endometrial cancer cells after phytochemical action. Asparanin A (AA) is a plant compound found in Asparagus officinalis L. that exhibits anti-inflammatory and antibacterial properties. Numerous studies have confirmed its potential to inhibit cancer cell growth through mechanisms such as inducing cell cycle arrest, apoptosis, and autophagy, as well as inhibiting metastasis ( Zhang et al., 2021 ). Zhang et al. conducted a study where they extracted AA from asparagus and observed its inhibitory effects on human EC Ishikawa cells both in vitro and in vivo . Following AA treatment, the levels of p16, p21, and p27 were up-regulated, while the levels of checkpoint kinase 1 (CHK1), Cyclin D1/CDK6, and Cyclin E1/CDK2 complexes were decreased. This suggested that the cells were arrested at the G0/G1 phase, leading to inhibition of cell proliferation. Moreover, AA treatment resulted in increased expression of Bax protein, Caspase-3, and Caspase-9, as well as decreased expression of Bcl-2 protein in cancer cells. These changes promoted the mitochondrial pathway of apoptosis due to the effects of ROS and Cyto C release. It is worth noting that both cell arrest and apoptosis are regulated by the PI3K/AKT pathway ( Zhang et al., 2020 ). Further analysis of proteins associated with invasion and metastasis revealed an increase in the expression of E-cadherin, while the expression of vimentin, MMP-2, and MMP-9 decreased. This suggests that AA effectively inhibits the migration and invasion of Ishikawa cells by suppressing EMT, which is mediated through the Ras/MEK/ERK pathway ( Zhang et al., 2021 ). In summary, AA has the potential to be used as a natural dietary drug for the treatment of endometrial cancer. Genistein, a naturally occurring flavonoid, is commonly found in Leguminosae species, including soybeans. This soybean isoflavone has been proven to be safe and can affect a variety of molecular targets, regulating various signaling pathways and demonstrating good anti-cancer efficacy. Due to its structural similarity to endogenous estrogen, genistein plays a crucial role in protecting women’s health and preventing women’s diseases ( Tuli et al., 2019 , Yu et al., 2021 ). Studies have reported that genistein can significantly inhibit the phosphorylation of EGFR in endometrial cancer cells. As EGFR is a key player in a complex signaling cascade, its inhibition directly leads to the blockade of cancer cell proliferation and differentiation. Additionally, the phosphorylated tyrosine 1173 of EGFR serves as the docking site for the PI3K/Akt signaling pathway, which further inhibits the PI3K/Akt and NF-kB signaling pathways, ultimately inducing apoptosis of endometrial hyperplasia cells ( Shukla et al., 2015 ). In addition, genistein inhibited cell proliferation by inducing G2-M phase cell cycle arrest and upregulated the expression of forkhead box protein O1 (FOXO1), a tumor suppressor located downstream of progesterone receptor (PR) signaling. In addition, genistein induced prolonged PR expression and inhibited cell proliferation in an estrogen receptor (ER)-independent manner. The enhanced expression of the progesterone receptor plays a crucial role in anti-tumor activity ( Yoriki et al., 2022 ). Genistein serves as a safe and effective plant compound that has the potential to treat or prevent endometrial cancer. Juglone, a natural phenolic compound found in Juglandaceae walnut, has been utilized in the treatment of skin disorders such as eczema and tinea. It possesses various properties including anti-oxidative stress, anti-aging, and potential cancer treatment effects ( Ahmad and Suzuki, 2019 , Wang et al., 2019 ). Zhang et al. investigated the impact of juglone on human endometrial cancer Ishikawa cells and discovered that it inhibited cell proliferation by causing S-phase arrest. This effect was achieved by upregulating p21 levels and decreasing CHK1, Cyclin A, cell division cycle 25 A (Cdc25A), and CDK2 levels. Furthermore, treatment with juglone resulted in a significant increase in intracellular ROS levels in Ishikawa cells, which influenced mitochondrial metabolism and triggered cell apoptosis through the mitochondrial pathway. This pathway was characterized by the down-regulation of Bcl-2 and Bcl-xL expression, while Bax, Bad, and Cyto C expression was up-regulated ( Zhang et al., 2019 ). Subsequent investigations revealed that Juglone induced ferroptosis and autophagy in EC Ishikawa cells, with a complex interaction between these processes. Juglone can induce ferroptosis in Ishikawa cells by increasing iron accumulation, depleting GSH, and promoting autophagy, which collectively leads to oxidative stress and cell death. Moreover, juglone is also involved in reducing the expression of MMP-9 and MMP-2, inhibiting the invasion and metastasis of Ishikawa cells through the inhibition of EMT ( Zhang et al., 2021 ). The diverse mechanisms of action observed in juglone indicate its potential as a promising natural anticancer agent for the treatment and prevention of endometrial cancer. Kaempferol, a flavonoid compound, is a traditional Chinese herbal medicine derived from Kaempferia galanga L.. It is commonly found in vegetables and fruits. It exhibits a wide range of pharmacological activities, including antibacterial, anti-inflammatory, antioxidant, and anti-cancer effects. Notably, kaempferol has been found to play a significant role in anti-cancer mechanisms. Epidemiological studies have demonstrated that a high intake of kaempferol is associated with a reduced incidence of various types of cancer ( Imran et al., 2019 , Imran et al., 2019 , Kumar, 2020 ). In the study, it was observed that the treatment of MFE-280 cell cycles with kaempferol resulted in the arrest of most cells in the G2/M phase, inhibiting the proliferation of cancer cells. Further investigations revealed a decrease in Bcl-2 protein levels and an increase in Bax protein levels, promoting cancer cell apoptosis. In addition, kaempferol inhibits the PI3K/AKT/mTOR pathway in cancer cells, which affects various cellular processes such as proliferation, growth, cell size, metabolism, and motility ( Alzahrani, 2019 , Lei et al., 2019 ). Furthermore, estradiol hormone primarily induces nuclear expression of ER α and survivin, thereby preventing apoptosis in EC cells. However, when cells were treated with kaempferol, it inhibited the induction of survivin by estradiol and led to apoptosis ( Chuwa et al., 2018 ). Kaempferol exhibits diverse mechanisms of action and holds significant potential as a natural drug. Its wide range of applications and promising research prospects make it an area of great interest. Ginger, a commonly used herb and spice, is frequently employed for treating ailments such as colds, diarrhea, nausea, and vomiting. Fresh ginger contains the highest amount of 6-gingerol, which can be converted to 6-shogaol through dehydration or thermal lysis. 6-shogaol possesses notable antioxidant, anti-inflammatory, and anti-cancer properties ( Bischoff-Kont and Fürst, 2021 , Ko et al., 2019 ). Ma et al. demonstrated that 6-gingerol had an inhibitory effect on the viability of EC Ishikawa cells. Treatment of Ishikawa cells with 6-shogaol resulted in decreased expression levels of CyclinE, CDK2, CyclinB, and Cdc2 proteins associated with the G2/M phase, while p53 and p21 were up-regulated, leading to the inhibition of cell proliferation. Failure to repair damaged cells promptly may induce cell cycle arrest, triggering the production of ROS, which in turn activates key endoplasmic reticulum (ER) response biomarkers linked to mitochondria and ultimately regulates relevant genes and proteins. This cascade of events resulted in increased levels of Bax protein, Caspase-3, and Caspase-9, while the level of Bcl-2 protein decreased ( Ma et al., 2020 ). In addition, 6-shogaol inhibited the invasion and metastasis of cancer cells in EC Ishikawa cells by reducing the expression of MMP-2 and MMP-9 through the regulation of the PI3K/AKT-related signaling pathway ( Ma et al., 2022 ). 6-Shogaol shows promise as a natural compound that could be targeted for the treatment or prevention of endometrial cancer. Capsaicin significantly reduced the viability and migration of UCEC cells and inhibited the expression of high expression gene GATA1 ( Lin et al., 2022 ). Chrysin can induce autophagy and apoptosis in endometrial cancer cells by increasing oxidative stress and inhibiting the Akt/mTOR signaling pathway ( He et al., 2021 ). Shikonin inhibits the proliferation and induces apoptosis of endometrial cancer cells by inhibiting the expression of miR-106b and blocking the PTEN/AKT/mTOR signaling pathway ( Huang & Hu, 2018 ).

Cancer is a significant public health issue worldwide and is responsible for the highest number of deaths in many countries. Among women, breast cancer has now become more prevalent than lung cancer, making it the most frequently diagnosed cancer ( Siegel et al., 2023 , Sung et al., 2021 ). Additionally, cervical cancer, endometrial cancer, and ovarian cancer are also prevalent malignant tumors affecting female reproductive organs ( Jiang, Tang, & Chen, 2018 ). Currently, the conventional treatment methods for cancer include surgery, chemotherapy, hormone therapy, immunotherapy, and more ( DeSantis et al., 2014 , Johnson et al., 2018 ). However, these treatments may not be suitable for all patients and can have numerous adverse reactions or toxic side effects. Several long-term side effects such as gastrointestinal discomfort, polyneuropathy, musculoskeletal pain, long-term fatigue, and cognitive impairment were frequently mentioned ( Berliere et al., 2021 , Joly et al., 2019 , O'Reilly et al., 2020 , Salata et al., 2021 ). For more detailed information, please refer to Table 1 . In contrast, phytochemicals offer a wide range of sources, low toxicity, minimal side effects, and easy absorption, making them promising for clinical applications ( Johnson et al., 2018 , Naeem et al., 2022 ). Table 1 Side effects or adverse reactions of traditional treatments for four major female cancers. Cancers Means of treatment Side effects or adverse reactions References Breast cancer Surgery Postoperative pain Berliere et al., 2021 Chemotherapy Doxorubicin Nephrotoxicity, cardiotoxicity Wu et al., 2021 Anthracycline plus cyclophosphamide Delayed CINV, Nausea De Laurentiis et al., 2018 Paclitaxel Peripheral neuropathy Lai, Chao, Liu, Huang, & Tseng, 2022 Docetaxel Fluid retention Radiation therapy Heart disease, impaired DNA repair fidelity Alsbeih et al., 2021 , Taylor and Kirby, 2015 Endocrine therapy Hot flashes, sexual dysfunction, weight gain, musculoskeletal symptoms, bone density loss, depression, cognitive dysfunction, fatigue Franzoi et al., 2021 Immunotherapy Skin toxicity, autoimmunity and nonspecific inflammation. Bahreyni et al., 2020 , Silvestri et al., 2021 Cervical cancer Surgery Wound complications, vaginal vault complications, cardiac complications Obermair et al., 2020 Chemotherapy Apatinib Hypertension, proteinuria, hemorrhage, fatigue, hand-foot syndrome, leukopenia Xiao, Chen, Wang, & Yu, 2020 Pembrolizumab Hypothyroidism, decreased appetite, fatigue Chung et al., 2019 Immunotherapy Vulvitis Baettig et al., 2019 Brachytherapy Pain, vaginal bleeding Chen et al., 2021 Endometrial cancer Surgery Anxiety and depression Wang, Li, Tan, Zhai, & Chen, 2020 Chemotherapy Paclitaxel-doxorubicin-cisplatin (TAP), carboplatin plus paclitaxel (TC) Neutropenic fever, Neuropathy, Thrombocytopenia, Vomiting, Diarrhea, Metabolic toxicities Miller et al., 2020 Radiation therapy Constant diarrhea Klopp et al., 2018 Ovarian cancer Surgery Sepsis, pulmonary embolism Cham et al., 2019 Chemotherapy Platin analogs and taxanes Affects biology of normal cells Mikula-Pietrasik et al., 2019 Radiation therapy Ovarian damage Cosgrove & Salani, 2019 Side effects or adverse reactions of traditional treatments for four major female cancers. Traditional medicinal plants have long been recognized as a valuable source of various bioactive compounds such as terpenoids, steroids, flavonoids, and phenolic compounds. In recent years, significant advancements have been made in the investigation of the biological activities of natural drugs. The pharmacological effects of newly discovered compounds have proven to be crucial in the development of novel drugs ( Gu et al., 2022 , Hao and Xiao, 2020 ). Many of these phytochemicals have biological activities in the prevention of cancer occurrence and treatment of cancer, which is expected to improve the treatment efficiency and reduce adverse reactions in cancer patients ( Choudhari et al., 2020 , Ranjan et al., 2019 ). In recent years, phytochemicals have shown significant progress in preventing the initial stage of cancer and inhibiting cancer progression, including cell invasion and metastasis ( Koh, Ho, & Pan, 2020 ). They achieve this by inhibiting cell proliferation, regulating the cell cycle, interfering with multiple signaling pathways, inhibiting angiogenesis, and inducing apoptosis. Overall, plant compounds have demonstrated promising anti-cancer effects ( Naeem et al., 2022 ). Quercetin, a common flavonoid plant compound, has demonstrated inhibitory effects on multiple types of cancers. It can effectively arrest the cell cycle in the G1 phase, promote cell apoptosis and autophagy, and regulate pathways such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Wnt/ β -catenin, and mitogen-activated protein kinase/extracellular regulated protein kinase1/2 (MAPK/ERK1/2). Furthermore, it exhibits inhibitory effects on angiogenesis and other processes ( Jeong et al., 2009 , Rashidi et al., 2021 , Reyes-Farias and Carrasco-Pozo, 2019 , Shafabakhsh and Asemi, 2019 ). This review focuses on the regulatory mechanisms of certain phytochemicals concerning four types of female cancers: breast cancer, cervical cancer, endometrial cancer, and ovarian cancer. The aim is to demonstrate the potential of phytochemicals in the prevention and treatment of these cancers. The findings provide a scientific foundation for the future development of anti-female tumor drugs, as well as clinical treatment and prevention strategies. Additionally, this review highlights the significance of natural drugs in female cancer research, which will likely attract the attention of more researchers.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.