Polyphenols encompass a diverse group of organic compounds characterized by multiple phenolic groups (-OH) arranged in benzene rings or analogous structures. This category includes various bioactive plant metabolites like phenolic acids, flavonoids, lignans, anthocyanins, and others (Williamson, 2017; Cory et al., 2018).

Curcumin is the principal active compound derived from the underground rhizome of the traditional Chinese medicine Curcuma longa. It belongs to the phenolic acid subgroup within the polyphenol family. Studies by Cao, X et al. (Cao et al., 2022), have demonstrated that Curcumin induces ferroptosis in breast cancer cells by upregulating the expression of SLC1A5. The inhibition of SLC1A5 in MDA-MB-453 and MCF-7 cells resulted in decreased glutamine uptake, increased levels of lipid ROS, accumulation of lipid peroxidation products, and elevated intracellular Fe²⁺ levels. Similarly, Li, R et al. (Li et al., 2020), discovered that curcumin upregulates several ferroptosis-related target genes involved in REDOX regulation, particularly HO-1. The effective attenuation of curcumin-induced ferroptosis in breast cancer cells is achieved by inhibiting HO-1 using the specific inhibitor Zinc Protoporphyrin (ZnPP). This is demonstrated by a notable decrease in lipid peroxidation and an elevation in intracellular glutathione levels.

Xie Y et al. (Xie et al., 2022b), isolated various diflavone compounds with distinct structural forms from Seladella. Among them, Robustaflavone 7,5″-dimethyl ether (RF-A) exhibite the ability to induce ferroptosis in breast cancer cells by downregulating ACSL4 protein expression. Furthermore, RF-A promoted ferroptosis by upregulating VDAC2 protein expression and suppressing the expression of NEDD4 E3 ubiquitin ligase, leading to lipid peroxidation and ROS production (Xie et al., 2021).

Quercetin, another polyphenolic compound found in several plants and fruits such as onions, grapes, apples, and leafy green vegetables. It can activate the transcription of transcription factor EB (TFEB) in BC cells. This, in turn, stimulates the lysosomal degradation of ferritin, resulting in increased intracellular iron ion concentration and the induction of ferroptosis. (An and Hu, 2022).

Levistilide A (LA) is an active compound derived from Ligusticum wallichii, which has been shown to significantly enhance ROS-induced ferroptosis by activating the Nrf2/HO-1 signaling pathway (Jing et al., 2022).

Gallic acid (GA1) is a naturally occurring phenolic acid compound widely found in nature (Al Zahrani et al., 2020). Extensive research has revealed the remarkable antioxidant and anticancer properties of GA1. Alkyl gallate, a derivative of GA1, is commonly employed as an antioxidant additive in various food products (Dodo et al., 2008). A study has shown that the combination of low-level laser irradiation and GA1 treatment has been shown to induce ferroptosis in MDA-MB-231 cells by reducing GPX4 activity and promoting lipid peroxidation (Khorsandi et al., 2020).

Terpenes are natural compounds composed of multiple isoprene units (C5H8). Terpenoids can be classified into different groups based on the number of ring structures they contain. Terpenoids can be categorized into different groups based on the number of ring structures they possess. Monomeric terpenoids consist of a single ring structure, while diterpenoids and triterpenoids are characterized by two and three ring structures respectively (Yang and Dou, 2010). Each of these classes has distinct structures and biological activities.

Glycyrrhetinic acid (GA2), also known as 18-β-glycyrrhetinic acid, is the primary active compound derived from licorice. It exhibits a wide range of anticancer activities in various types of cancer. The cytotoxic and antitumor properties of GA2 are attributed to the presence of triterpene functional groups in its structure, namely, carboxylic acid (-COOH) and hydroxyl (-OH) groups (Roohbakhsh et al., 2016; Hussain et al., 2021). GA2 has been shown to induce the production of reactive oxygen species (superoxide and hydroxyl radicals) by activating NADPH oxidase and iNOS. Additionally, it reduces the antioxidant capacity of cells by down-regulating SLC7A11 expression and inhibiting GPX4. These actions subsequently promote lipid peroxidation mediated by reactive oxygen/nitrogen species (ROS/RNS) and trigger ferroptosis (Wen Y. et al., 2021).

Isoliquiritin (ISO) is a triterpenoid compound derived from licorice. Administration of ISO results in elevated levels of intracellular Fe²⁺, ROS, and malondialdehyde (MDA). Concurrently, it reduces the levels of GSH and the relative protein expression of GPX4 and xCT. It is proposed that ISO regulates ferroptosis by potentially inhibiting NF-κB signaling (Wang et al., 2023).

Eupaformosin is a sesquiterpene lactone compound isolated from Eupatorium cannabinum. In vitro and in vivo studies have demonstrated that eupaformosin induces ferroptosis by promoting the ubiquitination of mutant p53. p53 is a protein involved in cell cycle regulation and tumor suppression (Wei et al., 2022).

Arnicolide D is a sesquiterpenoid compound extracted from Centipeda minima, a traditional Chinese medicinal plant. Dihydroisotanshinone I is extracted from the dried root of Salvia miltiorrhiza. Both of them can activate ferroptosis by increasing the accumulation of Fe²⁺ and MDA while suppressing the expression of GPX4^{[71 72]}.

Dihydroartemisinin (DAT), an active metabolite derived from artemisinin and its derivatives (ARTs), has gained significant recognition as an effective drug for the treatment of malaria in clinical practice. DAT demonstrates enhanced bioavailability when compared to its natural counterpart. However, DAT has recently garnered increasing attention for its potential anticancer activity in addition to its antimalarial properties. Researchers have been intrigued by the promising anticancer effects exhibited by DAT, leading to a growing interest in exploring its therapeutic applications in the field of oncology (Dai et al., 2021). DAT has the ability to induce the degradation of ferritin through lysosomal pathways, consequently impacting iron homeostasis regulated by the iron regulatory protein/iron-responsive element (IRP/IRE) system. This process leads to an increase in the levels of free iron within cells, rendering them more susceptible to ferroptosis (Chen G-Q. et al., 2020).

DMOCPTL is a derivative of the natural product parthenolide found in plants like feverfew. It induces ferroptosis by ubiquitinating GPX4 (Ding et al., 2021). This process leads to the degradation of GPX4 and subsequent disruption of cellular antioxidant defense mechanisms.

There are other various classes of compounds that exhibit different effects on ferroptosis. These include two polysaccharides, one alkaloid, one Benzopyran (Coumarins), one Fatty acid compound (linolenic acid), and one Glycoside (Saponins).

Lycium barbarum polysaccharide (LBP) is extracted from the fruit of Chinese medicine Lycium barbarum. LBP induced ferroptosis by reducing the expression levels of SLC7A11 and GPX4 (Du et al., 2022).

Red ginseng polysaccharide (RGP) is one of the main active ingredients extracted from red ginseng. Similar to Lycium barbarum polysaccharide, red ginseng polysaccharide induced ferroptosis by reducing GPX4 expression. And the overexpression of GPX4 in TNBC cells would make cancer cells resistant to RGP (Zhai et al., 2022).

Alpha eleostearic acid (αESA) is extracted from tung seed of conjugated linoleic acid ester (Cui et al., 2018). αESA was found to induce ferroptosis in vitro by triggering an ACSL1-dependent increase in lipid hydroperoxides. At the same time, they administered tung oil to BC mice by gavage and found that tung oil significantly inhibited tumor growth. Gene sequencing of mice revealed a significant upregulation of ferroptosis-related genes, indicating that the inhibition of tumor growth in vivo was associated with cell death caused by αESA in vitro (Beatty et al., 2021).

Tetrandrine citrate (TetC) is a new tetrandrine salt with high water solubility, which can be extracted from the traditional Chinese medicine Tetrandrine. It drove BC cell ferroptosis by activating NCOA4-mediated ferritin phagocytosis and inhibiting GPX4 expression in BC cells (Yin et al., 2022).

Alloimperatorin is a coumarin compound extracted from Angelica dahurica, a traditional Chinese medicine. It had been found to promote the accumulation of Fe²⁺, ROS, and malondialdehyde. Meanwhile, it significantly reduced the mRNA and protein expression levels of SLC7A11 and GPX4. These findings indicate that alloimperatorin induces ferroptosis (Zhang J. et al., 2022).

Polyphyllin III is a natural saponin extracted from Chinese medicine Paris flos. Zhou Y et al. (Zhou et al., 2021), found that it exerted a proliferation inhibitory effect on MDA-MB-231 triple-negative BC cells mainly through ACSL4-mediated elevation of lipid peroxidation and induction of ferroptosis. At the same time, the study also found that Polyphyllin III treatment induced a protective upregulation of xcT, a negative regulator of ferroptosis.

Formosanin C (FC) is a diosgenin glycoside extracted from Rhizoma paridis with anticancer activity (Man et al., 2011). FC induces both autophagy and apoptosis in human lung cancer cells and multiple myeloma cells (Chen P. et al., 2022; Chu et al., 2023). Meanwhile, Chen HC et al. (Chen HC. et al., 2022), identified that FC was a potent ferroptosis inducer in MDA-MB-231 Cells. FC-induced ferroptosis in TNBC is associated with suppressed levels of the FPN, xcT, and GPX4. Ferritinophagy also plays an important role in FC-induced ferroptosis. In addition, FC enhanced the sensitivity of TNBC cells to cisplatin.

In 2003, Dolma et al. (Dolma et al., 2003), classic apoptotic features were not found in erastin-induced cell death. Erastin-induced cell death is considered as a novel form of non-apoptotic cell death. Dixon et al. (Dixon et al., 2012), named erastin-induced cell death as ferroptosis. At the same time, as GSH is an indispensable substrate for the antioxidant effect of GPX4, the activity of GPX4 will also be inhibited (Zhao et al., 2020). Huang P et al. (Huang et al., 2023), found that the combination treatment of erastin and TGF-β1 could mediate autophagy-dependent ferroptosis by inducing the formation of the BECN1-SLC7A11 complex. Meanwhile, Lee N et al. (Lee et al., 2021c), also found that the classical ferroptosis inducer RSL-3 was able to induce the occurrence of ferroptosis in breast cancer cells.

In recent studies, there is mounting evidence indicating the potential of statins as agents capable of inducing ferroptosis (Yao X. et al., 2021; Elakkad et al., 2021; Ning et al., 2021; Zhang Q. et al., 2022). Statins are potent inhibitors of HMGCR, which plays a crucial role in controlling cholesterol biosynthesis through the mevalonate pathway (MVA) (Yu et al., 2017). The mevalonate pathway is involved in the synthesis of selenoproteins, including the active center of GPX4. By inhibiting the mevalonate pathway, statins can regulate ferroptosis by simultaneously suppressing ROS and down-regulating the levels of GPX4 (Yao X. et al., 2021; Elakkad et al., 2021). Notably, YAO X et al. (Yao X. et al., 2021), demonstrated an enhanced therapeutic effect against TNBC by utilizing zwitterionic polymer-coated magnetic nanoparticles (Fe3O4@PCBMA) to deliver the ferroptosis-inducing drug simvastatin (SIM).

Metformin is the most widely used oral hypoglycemic drug in clinical practice, which is commonly used to treat type 2 diabetes. In recent years, metformin has been proved to have the effect of cancer treatment and prevention, such as liver cancer, BC, colon cancer, pancreatic cancer and so on (Heckman-Stoddard et al., 2017). The verification of clinical efficacy of metformin and the exploration of potential mechanisms have become the research hotspots in the field of cancer. Metformin can activate AMPK to inactivate mTOR, thereby reducing cell proliferation and inducing apoptosis and cell cycle arrest (Zhao et al., 2015; Heckman-Stoddard et al., 2017). At the same time, metformin can indirectly affect tumorigenesis by affecting insulin levels and inducing energy stress (Pernicova and Korbonits, 2014). In addition, recent studies have found that metformin can also exert anti-tumor effects by inducing ferroptosis. Yang J et al. (Yang et al., 2021), found that metformin reduced the protein stability of SLC7A11 by inhibiting its UFMylation process. In addition, metformin could act synergistically when combined with the xc-system inhibitor sulfasalazine. Non-coding RNA are a class of RNA molecules that are widespread in cells and are synthesized during transcription but not translated into proteins. Non-coding RNA can be divided into several subclasses, including long non-coding RNA (lncRNA), microRNA (miRNA), small interfering RNA (siRNA), small nuclear RNA (snRNA) and so on (Yan and Bu, 2021). Metformin was found to induce ferroptosis via non-coding RNA. In TNBC cells, metformin promoted ferroptosis by up-regulating miR-324-3p expression and targeting GPX4 inhibition (Hou et al., 2021). Meanwhile, metformin-induced ferroptosis is achieved through the downregulation of lncRNA H19 and the inhibition of autophagy (Chen J. et al., 2022).

Anti-tumor drugs encompass various types, including chemotherapy drugs and targeted drugs. Lapatinib has been approved for the treatment of ErbB-positive BC (Tolaney, 2014). It functions as a dual tyrosine kinase inhibitor, targeting both ErbB1 and ErbB2 tyrosine kinase receptors (Wood et al., 2004). On the other hand, siramesine is a sigma-2 receptor ligand originally developed for depression treatment (Heading C. Siramesine H Lundbeck, 2001). S MA et al. (Ma et al., 2016), discovered that the combination of siramesine and lapatinib induced ferroptosis by increasing the expression of transferrin and decreasing the expression of ferroportin-1 (FPN1). Meanwile, they found that cystine transport inhibition promotes siramesine and lapatinib-induced cell death.

Neratinib, an irreversible pan-TKI, targets EGFR/HER1, HER2, and HER4 of the ERBB tyrosine kinase family (Rabindran et al., 2004). It is approved for extended adjuvant therapy in HER2-positive breast cancer as a single agent and in combination with capecitabine for advanced or metastatic disease (Geyer et al., 2006; Kourie et al., 2017). In HER2-positive BC cells (TBCP-1) treated with Neratinib, the levels of ferritin and FPN1 increased by 2-fold and 1.6-fold, respectively. Intracellular iron concentration also showed a dose-dependent increase at 72 h, as demonstrated by ICP-MS analysis. These findings indicated the proferroptosis activity of neratinib in HER2-positive BC cells (Nagpal et al., 2019).

Etoposide is a semi-synthetic derivative of podophyllotoxin. It is commonly used to treat malignant tumors such as leukemia and lymphoma (Meresse et al., 2004). Its primary mechanism of action involves inhibiting cell growth by forming a complex with topoisomerase II (Baldwin and Osheroff, 2005). A recent study (Ozkan and Bakar-Ates, 2023a) discovered that the combination of etoposide and erastin synergistically induced ferroptosis. This effect may be achieved through the inhibition of glutathione peroxidase activity and alterations in the expression of the ferroptosis regulatory protein IREB2 and FPN1. IREB2 is a protein that responds to changes in intracellular iron levels by binding to IRE, which regulate the expression of ferritin and TFR.

Recent studies have unveiled numerous non-anesthetic effects of anesthetics, including anti-tumor activity, anti-inflammatory properties, and even an antidepressant effect (Caracas et al., 2009; Li et al., 2019; Smith-Apeldoorn et al., 2022). Among them, propofol stands out as one of the most commonly used intravenous anesthetics in clinical practice. Several investigations have indicated that the administration of propofol during surgery improved the prognosis of BC patients compared to inhaled anesthetics (Yap et al., 2019). Sun C et al. (Sun et al., 2022), discovered that propofol, propofol injection emulsion, and phosphopropofol disodium significantly enhanced the antitumor effects of doxorubicin and paclitaxel while inducing changes associated with ferroptosis. In MDA-MB-231 cells, propofol may promote ferroptosis through the p53-SLC7A11-GPX4 pathway.

Ketamine is a rapid-acting anesthetic widely utilized in surgery since 1970, possessing potential anti-tumor activity (Dundee et al., 1970). Its anti-cancer properties have been demonstrated in various cancer models (Duan et al., 2019; He et al., 2021). In a study by Li H et al. (Li et al., 2021), edu-positive breast cancer cells were treated with ketamine, resulting in a significant increase in ferroptosis markers. Ketamine inhibited the expression of GPX4 by attenuating KAT5 in the GPX4 promoter region. This attenuation led to the inhibition of histone H3 lysine 27 acetylation (H3K27ac) and RNA polymerase II (RNA pol II) enrichment, ultimately suppressing the expression of GPX4.

Lidocaine is a local anesthetic extracted from cocaine and widely used in clinical practice. Through the analysis of clinical samples from ovarian and breast cancer patients, Sun P et al. (Sun D. et al., 2021), discovered a downregulation of miR-382-5p expression, while observing an upregulation of SLC7A11 expression. Lidocaine downregulated SLC7A11 expression by enhancing miR-382-5p in the BC cells.

Salinomycin is a broad-spectrum antibiotic with antibacterial effects. Mai T et al. (Mai et al., 2017), found a synthetic derivative of salinomycin, which they named ironomycin (AM5). AM5 exhibited a more potent and selective activity against breast CSCs in vitro and in vivo, accumulates and sequesters iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle.

BETi belong to a class of compounds that effectively inhibit the BET protein family. By competing with acetylated histones for binding to BET proteins, BET inhibitors reduce oncogene expression, thereby inhibiting tumor cell proliferation and promoting apoptosis (Andrieu et al., 2016). The BET protein family comprises BRD2, BRD3, BRD4, and BRDT (Shi et al., 2014). Prominent examples of BETi include JQ1 and I-BET. Sui S et al. (Sui et al., 2019), discovered that (+)-JQ1 inhibited BRD4 expression by suppressing the histone methylase G9a or activating the histone deacetylase SIRT1. This inhibition of BRD4 expression enhanced the expression of ATG5 and LAMP1, leading to the induction of ferritin phagocytosis. Wang L et al. (Wang et al., 2021), observed that BEi JQ1 and I-BET 151 (I-BET) activated the JNK/ATF2 pathway in MDA-MB-231 breast cancer cells. Activation of ATF2 by BETi blocks BETi-induced ferroptosis in cancer cells by upregulating NRF2 expression. These findings suggested that inhibiting ATF2 or NRF2 may enhance BET-induced ferroptosis, thereby augmenting the anticancer effects of BETi.

Phenazine derivatives belong to a substantial class of planar nitrogen-containing heterocyclic compounds. The key core structure is the pyrazine ring with two cyclic benzenes (1,4-diazabenzene) (Yan et al., 2021). These compounds exhibit diverse biological activities, including antimicrobial, antidepressant, anticancer, and other pharmacological effects (Gao et al., 2013; Krishnaiah et al., 2018). Yang Y et al. (Yang Y. et al., 2022), conducted a screening of phenazine library compounds targeting breast cancer stem cells and identified three compounds (CPUL119, CPUL129, and CPUL149). These compounds effectively accumulate and sequester iron in lysosomes through their interaction with iron. Additionally, they regulate the expression of proteins involved in iron transport and storage (IRP2, TFR1, ferritin), triggering ferroptosis.

CB1 antagonists block the interaction of endocannabinoids, such as the endogenous CB1 agonist anandamide, with CB1 receptors by binding to the CB1 receptor. Li P et al. (Li et al., 2022), identified that CB1 antagonists regulated sensitivity of TNBC cells to ferroptosis by regulating SCD1-and FADS2-dependent fatty acid metabolism. Some CB1 antagonists, such as rimonabant, have been investigated in clinical trials for obesity, metabolic diseases, and drug abuse. However, rimonabant is no longer approved for medical use due to its psychiatric side effects, such as anxiety and depression (Christensen et al., 2007).

MI-463 is menin-mixed-lineage leukemia inhibitors, unexpectedly inducing the ferroptotic cell death of several cancer cell lines. MI-463 in combination with auranofin, a thioredoxin reductase inhibitor, induced ferroptosis through upregulation of HO-1 (Kato et al., 2020).

Furthermore, there are other compounds, such as nitroisoxazole-containing spiro [pyrrolidin-oxindole] derivatives (Liu et al., 2021). which have been identified as novel dual inhibitors of GPX4 and MDM2.