In the last decade, the Nomenclature Committee on Cell Death (NCCD) has meticulously examined an extensive body of literature, ultimately formulating a definition for cell death that incorporates considerations of morphology, biochemistry, and function. This definition remains applicable to the present day. In terms of functional characteristics, cell death modalities can be categorized into two types: accidental cell death (ACD) and regulated cell death (RCD). (Galluzzi et al., 2018). Ferroptosis, a novel type of regulated cell death, is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and pyroptosis, among others. Elevated levels of iron-dependent reactive oxygen species (ROS) result in the buildup of lipid peroxides, disrupting redox homeostasis and causing oxidative damage to cell membranes. This imbalance adversely impacts normal cellular processes, ultimately leading to ferroptosis (Xing et al., 2023).

In 2003, Dolma et al. reported that a new compound, erastin, could induce RAS-mutated human foreskin fibroblasts (BJeLRs) death. However, this pattern of cell death differs from classical apoptosis previously found. During erastin-induced cell death, there were observations of distorted mitochondrial morphology and the disappearance of mitochondrial cristae. (Dolma et al., 2003). However, no classic features of apoptosis, such as mitochondrial cytochrome c release, caspase activation, or chromatin fragmentation, are observed in RSL-treated cells (Yagoda et al., 2007; Yang and Stockwell, 2008). In Nine years later, this new mode of cell death was officially named ferroptosis by Dixon et al. (Dixon et al., 2012). Since then, researchers have continued to explore the relationship between ferroptosis and human disease. Although the specific mechanisms and physiological functions of ferroptosis have not been fully elucidated, increasing evidence indicates that ferroptosis is involved in multiple pathological conditions, such as ischemia‒reperfusion injury (Carlson et al., 2016), stroke mitigation and neurodegeneration (Hambright et al., 2017; Tuo et al., 2017), and cancer treatment (Conrad et al., 2016; Stockwell et al., 2017; Tonnus and Linkermann, 2017; Toyokuni et al., 2017). Several studies have shown that suppressing system xc- or GPX4 inhibits tumor growth and metastasis in various types of cancer (Yang et al., 2014; Zhang et al., 2019a). In addition, multiple tumor suppressors have been found to sensitize cells to ferroptosis. For example, p53 can enhance tumor ferroptosis by suppressing the transcription of the system xc-subunit SLC7A11 (Wang et al., 2016). Malignant mutations in oncogenes usually accelerate metastasis, protect cancer cells from apoptosis and increase resistance to common cancer therapies (Piccolo et al., 2014; Hansen et al., 2015). However, the finding that these same mutations sensitize cancer cells to ferroptosis brings new hope for cancer treatment (Wu et al., 2019).

Traditional Chinese medicine (TCM), a medical theory system gradually formed and developed through long-term medical practice under the guidance of ancient simple materialism and spontaneous dialectics, is one of the oldest medical systems in the world. It has condensed thousands of years of health-preserving concepts and practical experience. TCM and its natural extracts have been widely used to treat various diseases, making significant contributions to medical health worldwide. Traditional Chinese medicine has shown efficacy in treating acute pancreatitis (Ge et al., 2023), neurodegenerative diseases (Lin et al., 2023), and polycystic ovary syndrome (PCOS) (Liu et al., 2022). Myocardial infarction (MI) (Wang et al., 2023a), atherosclerosis (AS) and hyperlipidemia (HLP) (Chen et al., 2021a; Wu et al., 2023)develop through the activation of ferroptosis. Given the recent studies highlighting the association between ferroptosis and the inhibition of tumor cells, there is a growing suggestion that ferroptosis could be a potential target for anticancer therapy. (Chen et al., 2021b). Consequently, it is a novel and meaningful research direction to explore the ferroptosis induced by traditional Chinese medicine.

In this review, we list the traditional Chinese medicines and their natural extracts and prescriptions that can be used to treat different cancers. The mechanism of the ferroptosis pathway was investigated to guide rational clinical application, improve disease prognosis and reduce patient suffering caused by toxic side effects.

TCM can also be combined with other drugs to exert anticancer effects synergistically via ferroptosis (Table 3). DHA promotes lipid peroxidation and ROS accumulation through nanocarriers combined with tetrandrine (TET), and synergistically inhibits DOX-resistant breast cancer cell growth (Zhang et al., 2023). ART, another artemisinin derivative, in combination with Nrf2 inhibitors promotes ferroptosis in tumor cells, achieving a more potent anticancer effect without damaging normal cells. RSL3 or Artesunate alone in the mitochondria could inhibite GPX4 activity to trigger ferroptosis. While the mitochondria-targeting artemisinin/RSL3 nanomedicine, A/R-PLGA/CPT/DSSP, treatment resulted in the strongest GPX4 inhibition compared with RSL3-PLGA/CPT/DSSP or ART-PLGA/CPT/DSSP. Carbon centered free radicals and ROS are produced in mitochondria to induce ferroptosis (Yu et al., 2023). β-Elemene, derived and purified from the roots and stems of the traditional Chinese medicine turmeric, is classified as a second-class anticancer drug. It has been used to participate in the treatment of some cancers (Wang et al., 2012; Wang et al., 2019a; Xiaomeng et al., 2020; Chen et al., 2021a). β-Elemene as a complementary drug in combination with cetuximab inhibites tumor growth and migration of KRAS mutant CRC cells by inducing ferroptosis. (Chen et al., 2020c).

Ursolic acid (UA) is a naturally occurring triterpenoid that is widely found in common fruits and herbs. Previous studies have shown that UA can inhibit the proliferation of prostate, lung, pancreatic and other tumor cells by inducing apoptosis (Chen et al., 2019; Lin et al., 2020; Kornel et al., 2023). Ursolic acid not only synergized with low doses of cisplatin in a mouse osteosarcoma xenograft model, significantly reducing tumor growth, but also reduced cisplatin-induced weight loss in mice. Detailed molecular studies have shown that ursolic acid activates autophagy first, then degrades ferritin, intracellular ferrous ion overload, and triggers ferroptosis ultimately. In addition, ursolic acid elevated the ability of cisplatin to destroy DNA damage in osteosarcoma cells (Tang et al., 2021b). Notably, In another study, ursolic acid combined with sorafenib treatment of HCT116 resulted in accumulation of lipid ROS, and downregulation of the apoptosis-related proteins Mcl-1 and ferroptosis -associated protein SLC7A11. Therefore, these results suggest that the synergistic antitumor mechanism of sorafenib/UA may also trigger ferroptosis by inducing apoptosis. (Li et al., 2022).

Osthole, chemically known as 7-methoxy-8-(3-methyl-2-butenyl)-2H-1-benzopyran-2-one, is a natural coumarin extracted from Cnidium spp. and various other plants belonging to the Apiaceae family (Sun et al., 2021). An increasing number of studies have demonstrated that osthole has anticancer effects on a variety of cancers (Shokoohinia et al., 2018), including glioma (Huangfu et al., 2021), endometrial cancer (Liang et al., 2021), and colorectal cancer (Huang et al., 2014; Zhou et al., 2021). Zhou et al. revealed that osthole can reduce the phosphorylation of AMPK, Akt and mTOR in HCT116 and SW480 cells and induce Ferroptosis by inhibiting the AMPK/Akt/mTOR signaling pathway. Combinative treatment of β-elemene and cetuximab enhance anticancer effect of cetuximab. Thus osthole plays an antitumor role in colorectal cancer cells with KRAS mutations (Zhou et al., 2023a).

Sheng Mai Yin(SMY), as a decoction of traditional Chinese medicine, comes from the Jin Dynasty Chinese medicine classic “Medical Qiyuan,” which is mainly composed of Radix ginseng, Ophiopogon and Schisandra. According to the testing of researchers, it was found that the active ingredients of Sheng Mai Yin mainly include triterpenoid saponins, steroidal saponins, lignans, etc. (Zheng et al., 2009; Liu et al., 2016; Wang et al., 2020b; Xu et al., 2021b). Sheng Mai Yin has previously been reported to have therapeutic effects on acute lymphoblastic leukemia (Guo et al., 2023), cardiac hypertrophy (Ming et al., 2022), heart failure (Kan et al., 2022), type 2 diabetes mellitus (T2DM) (Li et al., 2019). In addition, Sheng Mai Yin has been shown to inhibit the toxic side effects of doxorubicin and induced ferroptosis by modulating HMOX1, assisting cancer treatment and reducing patient complications (Meng et al., 2023).

Since ferroptosis was first defined in 2012, it has become a hot topic in the field of various diseases. The relationship between traditional Chinese medicine and ferroptosis and the corresponding regulatory mechanism in cancer are new research directions. Although several articles have reported the anticancer effects of Traditional Chinese Medicines (TCMs) by regulating ferroptosis, there is a limited summary of the underlying mechanisms. Combining these research results, the anticancer effects of TCMs through ferroptosis can be broadly categorized into four pathways: (1) inhibiting GPX4, (2) inhibiting system Xc−, (3) activating endoplasmic reticulum stress, and (4) imbalance of iron ion homeostasis (Figure 2).

Glutathione peroxidase 4 (GPX4), an antioxidant enzyme belonging to the GPX protein family, is a critical aspect in defending against ferroptosis. GPX4, a selenium-containing cysteine enzyme, serves as a key defense mechanism against this form of cell death. Both GSH and GPX4 are important molecules in regulating cellular oxidative environment. GSH is also an essential cofactor of GPX4, so GPX4 is inhibited when GSH is depleted. (Cao and Dixon, 2016). It uses reduced GSH to convert toxic phospholipid hydroperoxides (PLOOHs) into nontoxic phospholipid alcohols (PLOHs) (Jiang et al., 2021). When GPX4 decreases, with an increase in toxic PLOOH, the membrane structure is destroyed to stimulate ferroptosis. (Stockwell et al., 2020). The Tim-AIII-HSP90 complex triggers ferroptosis in non-small cell lung cancer (NSCLC) through targeting ubiquitination and degradation of GPX4 (Zhou et al., 2023b). Anomanolide C (AC) reduces the expression of GPX4 through ubiquitination and inhibits triple-negative breast cancer (TNBC) proliferation and metastasis both in vitro and in vivo (Chen et al., 2023a). Paeoniflorin suppressd Nrl2 and GPX4 via upregulation of NEDD4L and ubiquitination of STAT3 (Nie et al., 2022). Dihydroisotanshinone I induces ferroptosis in Breast cancer cells by inhibiting GPX4, leading to depletion of intracellular glutathione and a sharp increase in GSSG(Ahmadi et al., 2020). Similarly,OP-B (Zhang et al., 2022) and cucurbitacin B (Huang et al., 2021)induce ferroptosis by inhibiting GPX4.

The cystine/glutamate reverse transport system (system xc -) exports glutamate out of the cell and imports cystine into the cell in equivalent proportions, which plays a key role in the synthesis of glutathione (GSH), an important antioxidant (Niu et al., 2021). Upon entering the cell, cystine undergoes rapid conversion to L-cysteine, playing a pivotal role as a key constituent in the synthesis of intracellular glutathione (GSH). Glutathione is a substance that contains γ- Tripeptides with amide bonds and thiol groups, as antioxidants, are present in almost every cell of the mammalian body. It serves to restore intracellular reduction‒oxidation (REDOX) balance subsequent to reactive oxygen species (ROS) production, thus preventing cellular damage from free radicals, peroxides, and lipid peroxides. Additionally, it acts as an essential substrate for the enzymatic activity of GPX4 (Niu et al., 2021). Inhibiting the Xc− system indirectly results in GSH depletion, disrupting endogenous antioxidant mechanisms and leading to a substantial accumulation of ROS, ultimately triggering ferroptosis (Yu et al., 2017). Iron overload, accumulation of reactive oxygen species (ROS) and phospholipid hydroperoxides (PLOOH), initiation of Fenton reaction and further release of PLOOH are markers of Ferroptosis (Conrad and Pratt, 2019; Liang et al., 2022). SLC7A11, an amino acid transporter, regulates cystine uptake and the biosynthesis of glutathione and promotes the establishment of the antioxidant defense system. Targeted inhibition of SLC7A11 promotes intracellular lipid peroxide accumulation, induce tumor cell ferroptosis, and enhances sensitivity to immunotherapy, radiotherapy, and chemotherapy (Koppula et al., 2021; Yan et al., 2023). Dihydroartemisinin downregulate the level of PRIM2/SLC7A11 axis so that induce ferroptosis and inhibits the proliferation of lung cancer cell (Yuan et al., 2020). Gallic acid inhibit SLC7A11 and Wnt/β-catenin signaling to promote hepatocellular carcinoma ferroptosis (Xie et al., 2023). Qingrehuoxue Formula activated GSK-3β phosphorylation while reduced GSH and SLC7A11 level. Ferroptosis in NSCLC is subsequently activated with the accumulation of ROS and MDA (Xu et al., 2023). Curcumin suppresses breast cancer by elevating solute carrier family one member 5 (SLC1A5) and enhanced glutamine uptake (Cao et al., 2022).

Endoplasmic reticulum (ER) stressis a cellular response triggered by protein misfolding, accumulation of unfolded proteins, and disturbances in calcium homeostasis within the ER lumen. This activates unfolded protein responses, ER overload responses, and, in severe cases, apoptosis (Wei et al., 2021). There is increasing evidence suggesting a close relationship between ferroptosis and endoplasmic reticulum (ER) stress (Dixon et al., 2014). Moreover, the mechanism by which certain natural products induce ferroptosis is closely related to endoplasmic reticulum (ER) stress (Lu et al., 2021b). Saikosaponin A (SsA) (Lan et al., 2023) and the sophoridine derivative 6j (Tian et al., 2023) induced ferroptosis in hepatocellular carcinoma (HCC) cells by activating ER stress. Artesunate (ART) enhances ferroptosis in Burkitt’s lymphoma cell lines by activating the ATF4/CHOP/CHAC1 pathway, an endoplasmic reticulum stress response (Wang et al., 2019b).

Some studies have suggested that ferroptosis is an autophagy-dependent form of cell death. Excessive autophagy can activate ferroptosis through the accumulation of iron ions or lipid reactive oxygen species (ROS). Ferritin autophagy, a process in which ferritin is degraded through autophagy, has been identified as triggering ferroptosis in various cancer cells (Gao et al., 2016; Hou et al., 2016). Luteolin (Fu et al., 2023), Rh4 (Wu et al., 2022) and ursolic acid (Tang et al., 2021a)promote ferroptosis by increasing autophagy. Ferritin is a cytoplasmic iron storage protein, negative feedback protein of Ferroptosis. It consists of two subunits, ferritin heavy chain 1 (FTH1) and ferritin light chain (FTL) (Xing et al., 2023). When ferritin autophagy degrades, it releases large amounts of free ferrous ions that combine with hydrogen peroxide to trigger the Fenton reaction that activates Ferroptosis (Dixon et al., 2012). Therefore, the death mode of ferritinophagy is essentially an iron metabolism disorder in cells, and iron homeostasis is unbalanced. Luteolin demonstrates an anticancer effect on clear renal cell carcinoma by upregulating heme oxygenase-1 (HO-1) expression and activating labile iron pool (LIP)directly, thus triggering ferroptosis (Han et al., 2022b).

In addition to the four main pathways mentioned above earlier, there are other ways of regulation (Figure 3). Erianin has the capacity to induce ferroptosis in renal cancer stem cells by promoting the N6-methyladenosine modification of ALOX12/P53 mRNA (Shen et al., 2023). Curdione can activate ferroptosis by enhancing the methylation of SLC7A11 mRNA and HOXA13 mRNA (Wang et al., 2023b). Erianin triggered ferroptosis in lung cancer cells by activating Ca2+/CaM signaling (Chen et al., 2020c). Heme activates artemisinin to generate alkyl radicals and/or ROS in mitochondria of cancer cells. RSL-3 inhibits GPX4 and further induces mitochondrial lipid peroxidation (Yu et al., 2023). AMP-activated protein kinase (AMPK) has been shown to inhibit tumor growth by resisting ferroptosis in some studies (Lee et al., 2020). Yi et al. have suggested that upregulation of PI3K-AKT-mTOR signaling inhibit ferroptosis though SREBP-mediated lipogenesis (Yi et al., 2020). Activation of PI3K/AKT/Nrf2 was shown to improve cognitive impairment after cerebral ischemia by up-regulating GPX4 to inhibit ferroptosis (Fu et al., 2022). Similarly, osthole decreases AMPK phosphorylation and exactly promotes ferroptosis in KRAS-mutant colorectal cancer cells (Zhou et al., 2023a). These regulatory pathways involving key physiological and biochemical targets shed light on whether we might be able to use related factor inhibitors to aid in cancer prevention in the future. Certainly, this needs to be studied more thoroughly and in conjunction with clinical trials.

Indeed, several researchers have employed nanoparticles as tools to induce ferroptosis in tumor cells. The unique properties of nanoparticles make them promising agents for targeted therapeutic strategies, including the induction of ferroptosis in cancer cells (Jiang et al., 2021). For example, Ni et al. used atranorin complexes comprising superparamagnetic iron oxide nanoparticles (SPIONs) (Atranorin@SPION) to induce ferroptosis in GCSCs by decreasing the expression level of the Xc⁻/GPX4 axis and enhancing the 5-hydroxymethylcytosine modification of mRNAs in the pathway, thereby achieving therapeutic effects on gastric cancer (Ni et al., 2022b). Additionally, Yu et al. first demonstrated that artemisinin, a mitochondrial targeting agent, was much more toxic in vitro and in vivo than free artemisinin and non-targeted artemisinin nanodrugs against a variety of cancer cells, including MCF-7, HeLa, HepG2 and C6 cells. Mitochondrial artemisinin toxicity is mainly caused by free radicals and/or ROS-related apoptosis associated with artemisinin induced ferroptosis (Yu et al., 2023).

Some studies have also compared the effects of TCMs with classical ferroptosis inducers RSL-3 or erastin, which tend to increase the sensitivity of tumor cells to ferroptosis, resulting in mutual promotion (Table 2). Additionally, TCMs not only promote anticancer effects alone but also produce additive or synergistic effects when combined with Western medicines (Table 3). On the one hand, TCMs enhance the inhibition of tumor growth and metastasis by targeting iron death, and on the other hand, they alleviate the toxic side effects caused by chemotherapy drugs. After all, drug toxicity is an important consideration in terminal treatment options for cancer patients. These advantages make TCMs promising antitumor drugs.

Despite rapid and promising advances in research into the role of TCMs in iron death in cancer therapy, implementation into clinical use remains challenging. Activating ferroptosis can kill cancer cells, but whether normal tissues are damaged at the same time raises concerns about potential complications associated with the use of iron death inducers (Sui et al., 2019). Moreover, there are still doubts about the nonstandard compatibility, inaccurate dosage and nonsingle extract of traditional Chinese medicine. While Traditional Chinese Medicines (TCMs) and their active ingredients have been reported to have regulatory effects on ferroptosis, encompassing additional targets, stable structures, high safety, low cost, and easy availability, there is a notable insufficiency in the accumulation of related studies. Clinical trials are also lacking, and for many drugs, the mechanisms of action have not been fully elucidated. Therefore, to apply TCMs more rigorously and scientifically in the clinical treatment of cancer, future research should include additional large sample multicenter double-blind randomized controlled trials and related molecular cell biology experiments to further examine the mechanism of action, effectiveness and safety of TCMs. We hope that eventually TCMs can really slow down the progression of the disease, alleviate the suffering of patients, and improve the quality of life.