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V体育官网入口 - Tanshinone IIA induces ferroptosis in colorectal cancer cells through the suppression of SLC7A11 expression via the PI3K/AKT/mTOR pathway

Tingrui Ge1, Huazhuan Li1, Ping Xiang1, "V体育平台登录" Dong Yang1, Jingyi Zhou1 & …Yonggang Zhang1 Show authors European Journal of Medical Research volume 30, Article number: 576 (2025) Cite this article VSports app下载.

Abstract

VSports app下载 - Background

Colorectal cancer (CRC) is a malignant tumor of the digestive system with high incidence rate and mortality. Tanshinone IIA (Tan IIA) plays an anti-cancer role in a variety of cancer cells. Here, we aimed to elucidate the therapeutic effects and potential mechanism of Tan IIA in CRC V体育官网.

Methods

OUMS23 cells were treated with 0, 5, 10, or 20 μM Tan IIA, and CRC mice were exposed to 20 μM Tan IIA + SLC7A11 plasmid. Edu and flow cytometry analyses were performed to assay cell proliferation and apoptosis, respectively. An Iron Assay Kit was used for determining total iron and Fe2+ levels in intracellular and tumor tissues. Lipid reactive oxygen species (ROS) production was evaluated by flow cytometry. SLC7A11 expression was analyzed by reverse transcription-quantitative PCR (RT-qPCR), Western blot assay, and immunohistochemistry (IHC) VSports手机版. The activation status of the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (TOR) pathway was determined by Western blotting.

V体育安卓版 - Results

Tan IIA suppressed CRC proliferation in a dose-dependent manner. Moreover, Tan IIA inhibited SLC7A11 expression in OUMS23 cells and tumor tissues. Functional assays showed that Tan IIA induces CRC apoptosis, ferroptosis, and ROS release in intracellular and tumor tissues, while SLC7A11 plasmid transfection reverses these effects. Furthermore, SLC7A11 plasmid reversed the effects of Tan IIA on tumor volume and weight in CRC subcutaneous tumors. Further experiments revealed that SLC7A11 plasmid abolished the effects of Tan IIA on the PI3K/AKT/mTOR pathway, as confirmed by increased phospho (p)-AKT and p-mTOR expression, as well as increased p-AKT/AKT and p-mTOR/ mTOR ratios V体育安卓版.

Conclusion (V体育2025版)

Tan IIA induces ferroptosis in CRC by suppressing SLC7A11 expression through the PI3K/AKT/mTOR pathway V体育ios版. Therefore, Tan IIA may be an effective therapeutic agent in the treatment of CRC.

Introduction

CRC is a common malignant tumor of the digestive system originating from colorectal mucosa epithelium with high incidence rate and mortality [1, 2]. CRC mostly occurs in middle-aged men, most of whom are 40 to 70 years old. At present, the main treatment methods for CRC include surgery, chemotherapy, and immunotherapy [3,4,5]. Among them, chemotherapy is the preferred treatment. However, drug resistance and the inconspicuous early clinical manifestations of CRC before cancer metastasis develops hinder early diagnosis and treatment [6]. Chemoresistance is one of the major problems during chemotherapy for CRC and significantly limits the efficacy of the treatment and influences the prognosis of patients VSports最新版本. More than 90% of patients with metastatic cancer may fail chemotherapy due to drug resistance [7]. Therefore, reducing the incidence rate and mortality of CRC and finding effective treatment methods are urgent major clinical scientific issues.

Ferroptosis, a newly discovered cell death mode, is different from cell apoptosis, cell necrosis, autophagy, and other death modes [8]. An abnormal increase in cellular iron levels may lead to imbalances in redox homeostasis and lipid peroxidation of the cell membrane, eventually leading to cell death [9]. Ferroptosis involves many physiological and pathological processes, including cancer cell death, neurotoxicity, and T cell immunity [10, 11]. It also plays an important role in the occurrence and development of various diseases [12, 13]. Shin et al. showed that nuclear factor erythroid 2-related factor 2 (Nrf2) inhibition reverses resistance to glutathione peroxidase 4 (GPX4) inhibitor-induced ferroptosis in head and neck cancer [14] V体育平台登录. Yang et al. revealed that cetuximab promotes Ras-selective lethal 3 (RSL3)-induced ferroptosis by suppressing the Nrf2/heme oxygenase 1 (HO-1) signaling pathway in KRAS mutant CRC [15]. However, the specific mechanism of ferroptosis in CRC needs to be further explored.

Tan IIA, a widely used extract of Salvia miltiorrhiza, has a good inhibitory effect on tumor proliferation, migration, and angiogenesis [16]. Nie et al. found that Tan IIA regulates human acute myeloid leukemia cell proliferation, cell cycle, and apoptosis through the microRNA (miR)-497-5p/AKT3 axis [17]. Zhou et al. reported that Tan IIA suppresses ovarian cancer growth both in vitro and in vivo [18]. Qi et al. showed that Tan IIA markedly decreases the ATP level, glucose uptake, and lactate production in non-small cell lung cancer cells in vitro, and that it inhibits tumor growth in a xenograft model in vivo [19]. Moreover, Tan IIA induces ferroptosis in gastric cancer both in vitro and in vivo [20] VSports注册入口. Previous studies also evidenced Tan IIA is a vital regulator in CRC [21,22,23]. Qian et al. showed that Tan IIA alleviates the biological characteristics of CRC via activation of the ROS/c-Jun N-terminal kinase (JNK) signaling pathway [24]. Tan IIA also effectively inhibits CRC angiogenesis in vivo [22, 23]. However, the effects of Tan IIA on ferroptosis in CRC remain unknown.

Multiple pathways are involved in the progression of CRC [24,25,26]. PI3K/AKT/mTOR signaling pathway plays a key role in cancer development including proliferation, survival, metastasis, and angiogenesis [27]. PI3K/AKT/mTOR pathway is overexpressed and considered as a therapeutic target for colorectal cancer [28] V体育官网入口. PI3K/AKT pathway inhibition could sensitize cancer cells to ferroptosis induction [29]. And recent studies have revealed that mTOR is closely related to the occurrence and development of ferroptosis [30, 31]. Moreover, Tan IIA can suppress PI3K/AKT/mTOR pathway in several cancer cells [32, 33]. In this study, PI3K/AKT/mTOR pathway was analyzed.

Here, we aimed to analyze the effects of Tan IIA on ferroptosis in CRC and to clarify the potential mechanism VSports在线直播. Our findings provide a therapeutic basis for CRC therapy.

Materials and methods

Cell culture

OUMS23 (a human CRC cell line) cells were obtained from ATCC and cultured in DMEM medium (Gibco) containing 5% FBS (AS1044, ASPEN) and 1% penicillin/streptomycin at 37 °C with 5% CO2. Cells were treated with Tan IIA (0, 5, 10, and 20 μM) for 48 h [34]. Tan IIA was obtained from MedChemExpress (HY-N0135, purity 99.78%) and dissolved in DMSO for use.

EdU assay

To determine cell proliferation, EdU assay was performed. Briefly, OUMS23 cells were plated into 96-well plates and cultured for 2 h. Then, the cells were exposed to 50 μM EdU and fixed with 4% paraformaldehyde for 20 min. After that, the supernatant was removed by centrifugation for 5 min, and the cells were stained using an Apollo reaction kit. The results were analyzed using a fluorescence microscope.

VSports注册入口 - MTT assay

To determine the effect of Tan IIA on normal human intestinal epithelial cells (HIEC6), MTT assay was performed. Briefly, after treatment, HIEC6 cells were cultured into 96-well plates and incubated for 48 at 37 °C. Then, 10 μl MTT solution was added to each well and continuously incubated for further 4 h. And 100 μl DMSO was added to each well to dissolve the formazan product. Finally, the optical density (OD) at the wavelength of 570 nm was measured by a multifunctional plate reader (BioTek, Richmond, USA).

FCM assay

To determine the effect of Tan IIA on OUMS23 cell apoptosis, FCM assay was applied. After digesting with trypsin, OUMS23 cells were collected by centrifugation at 4 ℃ for 5 min. Then, the cells were washed twice with PBS (AS1044, ASPEN) and stained using the Annexin V/propidium iodide (PI) Apoptosis Detection Kit (Beyotime). After that, the cells were gently mixed and cultured for 20 min at room temperature without light. Annexin V-FITC and PI fluorescence were measured using a FACSCalibur flow cytometer (BD Technologies).

Iron assays

To determine the total iron and Fe2+ levels in OUMS23 cells and tissues, iron assay was performed. The Iron Assay Kit (Elabscience) was used to measure total iron and Fe2+ levels in OUMS23 cells and tissues. The iron assay buffer and iron reducer were successively added to the cells and tissues according to the instructions. Then, the samples were thoroughly mixed and cultured for 30 min after the addition of iron reducer without light and an iron probe. Lastly, the absorbance was measured at 593 nm.

Lipid ROS assay

After digesting with trypsin, OUMS23 cells were collected by centrifugation at 4℃ for 5 min. Then, the cells were treated with DCFH-DA dye solution and cultured for 30 min. Finally, fluorescence was examined using FACSAria II flow cytometer (BD Technologies).

RT-qPCR analysis

RNA from OUMS23 cells and tissues was isolated using the TRIpure Total RNA Extraction Reagent (EP013, ELK Biotechnology) as per the manufacturer’s instructions. Then, the total RNA was reversed to cDNA using an EntiLink™ 1 st Strand cDNA Synthesis Super Mix (ELK Biotechnology) according to the instructions. SLC7A11 and GAPDH expression levels were determined using the following specific primers:

  • H-ACTIN, F-5′-GTCCACCGCAAATGCTTCTA-3′ and

  • R-5′-TGCTGTCACCTTCACCGTTC-3′;

  • SLC7A11, F-5′TGTGGGGTCCTGTCACTATTTG-3′ and

  • R-5′-GATATCACAGCAGTAGCTGCAGG-3′.

Thermocycling conditions used for qPCR were as follows: initial denaturation at 95 °C for 30 s; followed by 40 cycles of 10 s at 95 °C, 30 s at 58 °C and 30 s at 72 °C; and a final extension for 10 min at 72 °C. Relative changes in target gene expression were analyzed using the 2−ΔΔCt method.

Western blot assay

OUMS23 cells and tissues were lysed for 30 min using RIPA buffer (AS1004, ASPEN). Proteins were then resolved by SDS-PAGE (AS1012, ASPEN) and transferred onto PVDF membranes. The membranes were blocked with 5% skimmed milk for 2 h to avoid non-specific binding and then incubated with primary antibodies against SLC7A11 (ab175186, 1:1000; Abcam), p-AKT (#9018; 1:1000; CST), AKT (#2938; 1:2000; CST), p-mTOR (#5536; 1:500; CST), mTOR (#2983, 1:1000; CST), or β-actin (TDY051, 1:10,000, Beijing TDY Biotech co., LTD.) at 4℃ overnight. After washing in TBST for three times, the membranes were incubated with secondary antibodies for 2 h. The protein signals were visualized by the addition of ECL (AS1059, ASPEN).

Cell transfection

OUMS23 cells were transfected with control and SLC7A11 plasmids using Lipofectamine® 3000 reagent (Thermo) for 48 h following the manufacturer’s protocol. After that, RT-qPCR was performed to evaluate cell transfection efficiency.

Experimental animals

Male BALB/c nude mice (4–6 weeks old, n = 6) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd and bred under standard conditions with free access to food and water. After subcutaneous injection of 2 × 106 OUMS23 cells into their axillary skin tissue, the mice were treated with Tan IIA (50 mg/kg) or Tan IIA in combination with the control or SLC7A11 plasmid. The mice were divided into four groups: Group I, Control group; Group II, 50 mg/kg Tan IIA; Group III, 50 mg/kg Tan IIA + control plasmid; and Group IV, 50 mg/kg Tan IIA + SLC7A11 plasmid. Seven days after OUMS23 cell injection, Tan IIA + control or SLC7A11 plasmid was intraperitoneally injected every other day, and the mice were killed 28 days after tumor cell inoculation. Mice were anesthetized and sacrificed by cervical dislocation. Death was verified by observing cardiac and respiratory arrest. Then, tumor volume and weight were measured. The experiments were terminated when the mice lost >15% of their body weight prior to the injection. None of the mice died during the study period. The experimental protocols were approved by the Ethics Committee of The First People's Hospital of Lianyungang.

"V体育官网" IHC analysis

Tissue samples were fixed with 4% paraformaldehyde for 24 h, paraffin embedded, and sectioned. Then, the slices were placed in citrate buffer and baked in a 62 ℃ oven for 90 to 120 min. After that, the slides were incubated with 5% BSA for 30 min, followed by incubation with SLC7A11 (1:200, Triple Eagle, 26864-1-AP) at 4 °C overnight. Next, the sections were incubated with the secondary antibody for 30 min and examined by optical microscopy (OLYMPUS).

V体育官网入口 - Statistical analysis

SPSS20.0 software was used for statistical analysis. The data are displayed as the mean ± standard deviation (SD) from three independent experiments, and comparisons between groups were carried out using one-way analysis of variance (ANOVA) or Student's t-test. Statistical significance was set at *P < 0.05 and **P < 0.01.

"VSports注册入口" Results

Tan IIA suppresses OUMS23 cell proliferation and stimulates apoptosis in a dose-dependent manner

First, the effect of Tan IIA on normal human intestinal epithelial cells (HIEC6) was detected by MTT assay, and the results indicated that Tan IIA (0, 5, 10, and 20 μM) has no toxic effect on HIEC6 cells (Supplementary Fig. 1). We then analyzed the effects of Tan IIA on the proliferation and apoptosis of CRC cells. OUMS23 cells were exposed to Tan IIA (0, 5, 10, and 20 μM) for 48 h. The results from the Edu assay showed that Tan IIA inhibited OUMS23 cell proliferation in a dose-dependent manner (Fig. 1A). In addition, as illustrated in Fig. 1B, Tan IIA induced more apoptotic cell death than the Control. These findings reveal the protective effects of Tan IIA on CRC cells.

Fig. 1
figure 1

Effects of Tan IIA on OUMS23 cell proliferation and apoptosis. OUMS23 cells were exposed to various concentration of Tan IIA. A OUMS23 cells were labeled with EdU and their proliferation was examined. B Flow cytometry analysis of apoptotic cells. **P < 0.01 vs. the 0 μM Tan IIA treatment group

Full size image

VSports注册入口 - Tan IIA induces ferroptosis in OUMS23 cells

Ferroptosis is a form of iron-dependent cell death, which is different from necrosis and apoptosis [8]. Several studies have suggested that ferroptosis is a vital modality of CRC cell death [15, 35]. Therefore, we investigated the effects of Tan IIA on ferroptosis in OUMS23 cells. Tan IIA treatment increased the intracellular concentrations of total iron (Fig. 2A) and Fe2+ levels (Fig. 2B) in OUMS23 cells. Furthermore, lipid ROS levels increased after Tan IIA treatment (Fig. 2C). Thus, these findings suggested that Tan IIA suppresses cell proliferation via the induction of ferroptosis in OUMS23 cells.

Fig. 2
figure 2

Effects of Tan IIA on OUMS23 cell ferroptosis. Total iron (A) and ferrous iron (B) levels were determined in OUMS23 cells after treatment with Tan IIA. C The generation of lipid ROS in OUMS23 cells was analyzed using flow cytometry analysis. *P < 0.05, **P < 0.01 vs. the 0 μM Tan IIA treatment group

Full size image

Tan IIA induces ferroptosis by regulating SLC7A11 expression in OUMS23 cells

Ferroptosis is related to many diseases and can be regulated by multiple critical factors, including SLC7A11 [36]. Thus, we examined whether Tan IIA affects SLC7A11 expression in OUMS23 cells. Tan IIA reduced the expression of SLC7A11 in a dose-dependent manner in OUMS23 cells (Fig. 3A, B). To further analyze the roles of SLC7A11 in OUMS23 cells, the cells were transfected with a control or SLC7A11 plasmid and exposed to 20 μM Tan IIA. As displayed in Fig. 3C, D, SLC7A11 expression was up-regulated in SLC7A11 plasmid-transfected cells. In addition, we observed that Tan IIA substantially decreased the SLC7A11 expression in OUMS23 cells (Fig. 3E, F) and increased the intracellular total iron (Fig. 3G), Fe2+ (Fig. 3H), and ROS (Fig. 3I) levels. However, these effects were significantly suppressed by transfection with the SLC7A11 plasmid.

Fig. 3
figure 3

Effects of SLC7A11 plasmid transfection on Tan IIA-induced OUMS23 cell ferroptosis. A, B RT-qPCR and Western blot analysis of SLC7A11 levels in the Control and Tan IIA groups. C, D SLC7A11 levels in control plasmid- and SLC7A11 plasmid-transfected cells were analyzed using RT-qPCR and Western blot assay. E, F Evaluation of SLC7A11 levels using RT-qPCR and Western blot in Tan IIA + control plasmid and Tan IIA + SLC7A11 plasmid groups. Total iron (G) and ferrous iron (H) levels were determined. I Flow cytometry analysis quantifying lipid ROS production in OUMS23 cells. **P < 0.01 vs. the 0 μM Tanshinone IIA treatment group; ##P < 0.01 vs. the Control plasmid group; &&P < 0.01 vs. the Control group; $, $$P < 0.05, 0.01 vs. the Tan IIA + control plasmid group

Full size image

V体育ios版 - Tan IIA induces ferroptosis by inhibiting SLC7A11 expression through the PI3K/AKT/mTOR pathway in OUMS23 cells

Previous reports have suggested that multiple pathways are involved in the progression of CRC, including the PI3K/AKT pathway [37]. Consistently, we found that Tan IIA inhibited the p-AKT and p-mTOR expression in a dose-dependent manner in OUMS23 cells (Fig. 4A), as well as the ratio of p-AKT/AKT and p-mTOR/mTOR (Fig. 4B, C). In contrast, we observed the opposite results in SLC7A11 plasmid-transfected cells (Fig. 4D, F). These findings suggested that the PI3K/AKT/mTOR pathway acts as a vital player in CRC progression.

Fig. 4
figure 4

The PI3K/AKT/mTOR pathway is involved in the progression of CRC. OUMS23 cells were transfected with SLC7A11 plasmid or control plasmid and exposed to 20 μM Tan IIA. A Western blot analysis of p-AKT and p-mTOR expression. B, C The p-AKT/AKT and p-mTOR/mTOR ratios. D Detection of p-AKT and p-mTOR levels. E, F Quantification of the p-AKT/AKT and p-mTOR/mTOR ratios. *,**P < 0.05, 0.01 vs. the 0 μM Tan IIA treatment group; ##P < 0.01 vs. the Control group; &&P < 0.01 vs. the Tan IIA + control plasmid

Full size image

SLC7A11 plasmid transfection reverses the effects of Tan IIA on the volume and weight of CRC subcutaneous tumors

Next, we conducted in vivo experiments to analyze the roles of SLC7A11 in CRC progression. The subcutaneous tumor models were treated with Tan IIA and infected with control plasmid or SLC7A11 plasmid. Figure 5A displays a representative diagram of the subcutaneous tumors. Moreover, tumor volumes and weights were measured. Tan IIA treatment decreased the volume and weight of the tumors in mice inoculated with OUMS23 cells. However, these tumor-suppressive effects were remarkably eliminated by SLC7A11 plasmid transfection (Fig. 5B, C). In conclusion, our data indicated that SLC7A11 overexpression blocks Tan IIA-mediated tumor inhibition.

Fig. 5
figure 5

Tan IIA suppresses CRC growth in vivo. A Representative images of the tumors are shown. B, C Tumor volumes and weights in each group were measured. **P < 0.01 vs. Control; ##P < 0.01 vs. Tan IIA + control plasmid

Full size image

SLC7A11 plasmid transfection reverses the effects of Tan IIA on ferroptosis in CRC subcutaneous tumors

We further analyzed whether SLC7A11 affects cell death through its effects on ferroptosis. As shown in Fig. 6, Tan IIA prominently reduced the total iron (Fig. 6A), Fe2+ (Fig. 6B), and ROS (Fig. 6C) levels in tumor tissues, and these effects were reversed by transfection with the SLC7A11 plasmid.

Fig. 6
figure 6

Effects of SLC7A11 plasmid and Tan IIA on ferroptosis in CRC subcutaneous tumors. Total iron (A), ferrous iron (B), and lipid ROS (C) levels in CRC subcutaneous tumors were determined. **P < 0.01 vs. Control; #, ##P < 0.05, 0.01 vs. Tan IIA + control plasmid

Full size image

V体育官网 - Tan IIA induces ferroptosis by inhibiting SLC7A11 through the PI3K/AKT/mTOR pathway in CRC subcutaneous tumors

We also determined the effects of SLC7A11 plasmid transfection on Tan IIA regulation of the PI3K/AKT/mTOR pathway in CRC subcutaneous tumors. Data from the IHC assay and RT-qPCR analysis demonstrated that Tan IIA significantly reduced the SLC7A11 mRNA and protein levels (Fig. 7A–C). Furthermore, the protein expression of p-AKT and p-mTOR (Fig. 7D), and the p-AKT/AKT and p-mTOR/mTOR ratio (Fig. 7E, F) in tumor tissues were decreased. However, these effects were eliminated by transfection with the SLC7A11 plasmid. These findings suggested that Tan IIA induces ferroptosis by inhibiting SLC7A11 expression via the PI3K/AKT/mTOR pathway in CRC.

Fig. 7
figure 7

Effects of SLC7A11 plasmid and Tan IIA on the PI3K/AKT/mTOR pathway in CRC subcutaneous tumors. A The expression of SLC7A11 as determined by IHC assays. B Quantification of SLC7A11 expression. C SLC7A11 levels measured by RT-qPCR. D Western blot analysis of p-AKT and p-mTOR expression. E, F Values of the p-AKT/AKT and p-mTOR/mTOR ratios. bar = 50 μm. **P < 0.01 vs. Control; ##P < 0.01 vs. Tan IIA + control plasmid

Full size image

"V体育ios版" Discussion

CRC is the third most common malignant tumor and the fourth leading cause of tumor-related death, with a high incidence rate and mortality [38]. The treatment methods of CRC include surgery, radiotherapy, molecular targeted therapy, and immunotherapy [39, 40]. At present, oxaliplatin is the first-line chemotherapy drug for CRC patients, but drug resistance remains an obstacle in the treatment of CRC [41]. At the same time, the symptoms of CRC are not obvious until metastasis develops, which also hinders early diagnosis. Therefore, new therapeutic targets for CRC are urgently needed.

Tan IIA is the main component isolated from Salvia miltiorrhiza. Tan IIA plays a protective role in angina pectoris and cerebral ischemia through its vasodilatory effect and anti-inflammatory activity [42]. In addition, Tan IIA regulates tumor development in gastric cancer [43], colon cancer [44], and CRC cancer [21]. In addition, Xie et al. found that the mechanisms of Tan IIA cytotoxicity include anti-proliferation, apoptosis induction, and endoplasmic reticulum stress induction in various cancer cell lines [45]. Our previous study revealed that Tan IIA significantly inhibits the proliferation and metastasis of CRC cells [46]. In this study, consistent with previous findings, we found that Tan IIA inhibits OUMS23 cell proliferation and induces apoptosis in a dose-dependent manner.

Ferroptosis, a newly discovered type of non-apoptotic programmed cell death that regulates cancer progression, may be a promising strategy for tumor treatment [8, 12, 35]. It is considered a beneficial therapeutic target for lung cancer and a new therapeutic target for bladder cancer [47]. Recent studies indicated that Tan IIA induces ferroptosis and ameliorates cisplatin resistance in gastric cancer cells through suppressing SLC7A11 expression [48, 49]. However, the effect of Tan IIA on ferroptosis in CRC remains unknown. Iron is a vital executor of ferroptosis. The intracellular iron level is regulated by iron regulatory transporters, and Fe2+ is particularly important for stimulating ferroptosis [42]. Therefore, we studied the effect of Tan IIA on ferroptosis in OUMS23 cells. Our data demonstrate that Tan IIA increases the concentration of total iron and Fe2+ in OUMS23 cells. GPX4 is the central mediator of ferroptosis and induces cancer cell death accompanied by the production of lipid ROS [50]. We found that Tan IIA-treated cells have increased lipid ROS levels. These findings indicate that Tan IIA induces ferroptosis in OUMS23 cells.

SLC7A11 is highly expressed in human tumors, including CRC [51]. SLC7A11 inhibition can induce ferroptosis. In contrast, SLC7A11 overexpression may protect cancer cells from ferroptosis. Sun et al. showed that lidocaine promotes ferroptosis in ovarian and breast cancer by targeting the miR-382-5p/SLC7A11 axis [52]. In addition, studies have shown that Tan IIA can promote ferroptosis by down-regulating the expression of SLC7A11 in breast cancer and gastric cancer [53, 54]. In our study, we found that Tan IIA decreases the expression of SLC7A11 in OUMS23 cells in a dose-dependent manner. To analyze the roles of SLC7A11 in OUMS23 cells, OUMS23 cells were transfected with control plasmid or SLC7A111 plasmid and exposed to 20 μM Tan IIA. SLC7A11 expression was down-regulated in Tan IIA-treated cells and increased in SLC7A11 plasmid-transfected cells. Moreover, SLC7A11 plasmid transfection reversed the effects of Tan IIA on ferroptosis, as confirmed by decreased intracellular total iron, Fe2+, and ROS levels. Thus, Tan IIA induces ferroptosis in CRC cells by inhibiting SLC7A11 expression.

In this study, PI3K/AKT/mTOR pathway was analyzed. Consistent with this, we found that Tan IIA inhibits p-AKT and p-mTOR expression and the ratio of p-AKT/AKT and p-mTOR/mTOR in OUMS23 cells in a dose-dependent manner. However, we observed the opposite results in the SLC7A11 plasmid transfection group. Our findings demonstrate that the PI3K/AKT/mTOR pathway plays an important role in CRC progression. The roles of SLC7A11 have been investigated both in vitro and in vivo. Based on the above findings, we established a nude mouse model of CRC subcutaneous tumors and clarified the potential regulatory mechanism between Tan IIA and SLC7A11. The xenograft tumor model was treated with Tan IIA and infected with control plasmid or SLC7A11 plasmid. We measured the volume and weight of solid tumors and found that the addition of the SLC7A11 plasmid reversed the effect of Tan IIA on tumor growth and ferroptosis in CRC subcutaneous tumors, suggesting that Tan IIA could inhibit CRC growth by regulating SLC7A11, and Tan IIA may be a potential therapeutic agent in the treatment of CRC. Immunofluorescence, RT-qPCR, and Western blot analyses revealed that the SLC7A11 plasmid reverses the effects of Tan IIA on the PI3K/AKT/mTOR pathway in CRC subcutaneous tumors.

There were also some limitations of the current study. First, only one CRC cell line (OUMS23) was used in this study to study the effect of Tan IIA on CRC cells, and studying more CRC cell lines will make the results of this study more convincing. Besides, the specific mechanisms underlying the regulatory effects of Tan IIA on SLC7A11, especially the potential involvement of microRNAs or other signaling pathways in this process has not been explored. Moreover, the subcutaneous xenograft tumor model in nude mice enables human tumor cells to find a living carrier to study the growth and metastasis of human tumor with the help of nude mouse. However, due to the lack of T cell immunity and heterogeneous growth environment, the subcutaneous xenograft tumor model in nude mice cannot fully represent the complex microenvironment of colorectal cancer.

Conclusions

Taken together, our findings demonstrate that Tan IIA induces ferroptosis by suppressing SLC7A11 expression through the PI3K/AKT/mTOR pathway in CRC. Our findings may supply a powerful experimental basis for the use of Tan IIA in the treatment of CRC, and Tan IIA may as a candidate for clinical treatment of CRC.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CRC:

Colorectal cancer

GPX4:

Glutathione peroxidase 4

HO-1:

Heme oxygenase 1

IHC:

Immunohistochemistry

JNK:

C-Jun N-terminal kinase

miR:

MicroRNA

mTOR:

Mammalian target of rapamycin

Nrf2:

Nuclear factor erythroid 2-related factor 2

PI:

Propidium iodide

PI3K:

Phosphatidylinositol 3-kinase

ROS:

Reactive oxygen species

RSL3:

Ras-selective lethal 3

RT-qPCR:

Reverse transcription-quantitative PCR

Tan IIA:

Tanshinone IIA

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Acknowledgements

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Funding

The present study was supported by 2021 Jiangsu Traditional Chinese Medicine Science and Technology Development Plan Project (grant no. MS2021065).

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V体育官网 - Authors and Affiliations

  1. Department of Colorectal Surgery, The First People’s Hospital of Lianyungang, No. 6 Zhenhua Road, Haizhou District, Lianyungang, 222002, China

    Tingrui Ge, Huazhuan Li, Ping Xiang, Dong Yang, Jingyi Zhou & Yonggang Zhang

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Contributions

Tingrui Ge contributed to Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Writing – original draft, and Writing – review & editing. Huazhuan Li contributed to Data curation, Resources, and Supervision. Ping Xiang contributed to Methodology, Software, and Visualization. Dong Yang contributed to Software and Supervision. Jingyi Zhou contributed to Formal analysis and Validation. Yonggang Zhang contributed to Data curation, Supervision, and Writing – review & editing. All authors read and approved the final manuscript.

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Correspondence to Yonggang Zhang.

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This study is reported in accordance with ARRIVE guidelines. This study was approved by Ethics Committee of The First People's Hospital of Lianyungang.

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Supplementary Information

Additional file 1.

40001_2025_2842_MOESM2_ESM.jpg

Additional file 2: Supplementary Fig. 1. Effect of Tan IIA on normal human intestinal epithelial cellswas detected by MTT assay.

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Ge, T., Li, H., Xiang, P. et al. Tanshinone IIA induces ferroptosis in colorectal cancer cells through the suppression of SLC7A11 expression via the PI3K/AKT/mTOR pathway. Eur J Med Res 30, 576 (2025). https://doi.org/10.1186/s40001-025-02842-7

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