Esketamine (ESK), a new psychoactive substance known for its strong hallucinogenic effect, has been detected in surface water worldwide. The toxicity of ESK to fish at a certain environmental concentration remains unclear. In this study, zebrafish embryos and ZF4 cells were exposed to ESK (0, 0.12, 1.02, and 10.6 μg L-1, marked by SC, LC, MC, and HC, respectively) for 14 days post fertilization (dpf) and 24 h, respectively. Biphasic dose responses induced by ESK were observed after 24 h of exposure. ESK-LC and ESK-MC obviously increased embryo area and length, height, and volume of yolk sac, whereas ESK-HC had the opposite effect. ESK-LC and ESK-MC appreciably upregulated the transcription and expression levels of vtg, disrupting the cell cycle after 24 h of exposure. After 14 dpf exposure, KEGG analysis indicated that circadian rhythm, nucleotide excision repair, and estrogen signaling pathways were the top three impacted pathways, with ESK significantly enhancing gene transcription in these three pathways, except for cyp7a1 and bh1he41. Correspondingly, ESK notably increased the VTG level, aligning with the relatively high affinity of estrogen receptors, as analyzed through molecular docking. Our research demonstrated that ESK exhibits developmental toxicity and endocrine-disrupting effects in zebrafish, highlighting the need to address its ecological toxicity in fish.

Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prognosis. We discovered that BMAL1 is a ferroptosis suppressor. Furthermore, it was also found to be overexpressed in AML patients, affecting the cell cycle and promoting tumor cell growth and progression. In this study, we further validated the association of BMAL1 with the progression and survival outcomes of AML. Lipidomic revealed that the levels of ceramide increased in AML cells following the depletion of BMAL1. Ceramide facilitated ferroptosis in AML cells. ASAH2 played a key role in this process. BMAL1 could not directly regulate ASAH2 but instead through IKZF2. Elevated levels of ceramide promoted the degradation of the ferroptosis protection molecule GPX4, ultimately promoting ferroptosis. Furthermore, ceramide treatment has been demonstrated to enhance the responsiveness of AML cells to sorafenib. In summary, this study elucidates that BMAL1 depletion remodels ceramide metabolism to regulate the sensitivity of AML cells to ferroptosis and targeted drug sorafenib.

Ferroptosis is a type of regulated cell death caused by oxidative imbalance of the intracellular microenvironment. This causes the accumulation of toxic lipid peroxides, depicted by iron overload and lipid peroxidation, which results in disease development. The affected cell population displays unique morphological and biochemical features, which are distinct from other modes of cell death, like apoptosis, pyroptosis, and necroptosis. The individual pathways of each of these modes are interrelated and tend to counterbalance each other in the mechanism of cell death. The process of ferroptosis is associated with disturbances in iron metabolism, in conjunction with glutathione peroxidase and lipid peroxidation, culminating in a reduction of antioxidant capacity and accumulation of lipid peroxides in the dying cell. It has been observed that even excess cellular levels of iron can cause cell death, where ferroptosis is initiated by diminishing the levels of glutathione and glutathione peroxidase 4, and thus leading to excess build-up of lipid reactive oxygen species (ROS). In the case of a neoplastic cell, ferroptosis along with its regulators tends to orchestrate cell death and also affects cancer progression by modulation of proliferation activity, apoptosis suppression, metastasis, and drug resistance. Comprehending the complex network of molecular processes implicated in ferroptosis regulation is vital for developing targeted therapies for diseases where ferroptosis plays a significant role.

The survival of patients with locally advanced and metastatic bladder cancer (BCa) is persistently low. Hence, new treatment options are urgently needed. Artesunate (ART) a derivative of artemisinin, used in Traditional Chinese Medicine, shows anti-tumor activity extending over a broad spectrum of human cancers. As we have previously shown, ART inhibits growth in cisplatin-sensitive (parental) and cisplatin-resistant BCa cells. However, how ART acts on the metastatic potential of BCa remained unclear. To clarify, we applied ART to parental and cisplatin-resistant RT4, RT112, T24, and TCCSup BCa cell lines. We examined tumor cell adhesion to vascular endothelium and immobilized collagen and evaluated chemotactic activity, migration, and invasive activity of the BCa cells. Adhesion receptors, integrin α and β subtypes, integrin-linked kinase (ILK), and focal adhesion kinase (FAK) were investigated. The functional relevance of integrin expression altered by ART was determined by blocking studies. ART significantly reduced tumor cell adhesion to vascular endothelium and immobilized collagen in parental as well as in cisplatin-resistant BCa cells. Depending on cell type, ART suppressed tumor cell motility and diminished integrin expression (surface and total). Functional blocking of integrins altered by ART reduced cell adhesion and invasion of the BCa cells. Thus, the metastatic potential of parental and cisplatin-resistant BCa cells was significantly inhibited by ART, making it a promising treatment option for patients with advanced or therapy-resistant BCa.

Lenvatinib has been employed in the treatment of advanced liver cancer; however, its clinical application is significantly impeded by frequent drug resistance. Recent studies have revealed that lenvatinib treatment triggers ferroptosis in liver cancer cells, providing a novel approach to addressing lenvatinib resistance. In this study, we initially validated the induction of ferroptosis by lenvatinib in liver cancer cells. Remarkably, protocadherin 17 (PCDH17), an adhesion-related protein, was found to be down-regulated in liver cancer, and overexpression of PCDH17 could induce ferroptosis in liver cancer cells. Importantly, silencing PCDH17 inhibited the impact of lenvatinib on liver cancer cell ferroptosis, while overexpression of PCDH17 had the opposite effect. These findings were further confirmed using a xenograft tumor model in BALB/c nude mice. Additionally, lenvatinib-resistant (LR) liver cancer cells were generated for additional validation purposes. It was observed that LR-liver cancer cells lost their susceptibility to ferroptosis induction by lenvatinib; however, overexpression of PCDH17 reactivated their sensitivity to ferroptosis. Corresponding results were also verified in BALB/c nude mice models. In conclusion, these results suggest that as a novel regulator of ferroptosis, PCDH17 can alleviate lenvatinib resistance and potentially enhance the therapeutic efficacy of lenvatinib in treating liver cancer.

Programmed necrosis, a controlled cell death method that bypasses resistance mechanisms that render apoptosis ineffective, is a potential cancer treatment target. Due to their diverse biological activities and low side effects, natural products are being explored as modulators of programmed necrosis pathways. This review highlights the potential of natural compounds to target cancer cells while preserving healthy tissues and their interaction with essential programmed necrosis mechanisms like ferroptosis and necroptosis. Recent developments have identified various types of programmable necrosis, including necroptosis, ferroptosis, pyroptosis, proptosis, mitochondrial permeability transition-driven necrosis, and oncosis. Natural compounds are increasingly being utilized as a primary source of anti-cancer medications, providing new cancer treatments. This review demonstrates the molecular mechanisms behind lipid peroxidation, mixed lineage kinase domain-like protein, and receptor-interacting protein kinases (RIPK1 and RIPK3) inducing cell death. Recent research has identified natural compounds like polyphenols, alkaloids, and terpenoids that can modulate pathways and benefit preclinical cancer models. The review underscores the potential of natural compounds in developing innovative cancer treatments by integrating pharmacology and cellular signaling knowledge. Integrating natural compound studies and programmed necrosis research presents a promising avenue for oncologists to overcome treatment resistance. Natural compounds have shown potential in developing programmed necrosis as a novel cancer treatment approach, enhancing therapeutic effectiveness and minimizing side effects through preclinical research, pharmacology, and molecular biology.

Ferroptosis, a form of non-apoptotic cell death, is emerging as a promising strategy for cancer therapy. Artesunate (ART), an extract obtained from the traditional Chinese medicine Qinghaosu, has been shown to exhibit anti-cancer activity by inducing ferroptosis in cancer cells. While previous research has focused on incorporating ART monomer into drug delivery systems for enhanced cancer targeting, this study presents 2-methacryloyloxyethyl ART polymer (poly(ARTEMA)), a novel polymer synthesized from ART for the first time. Our goal was evaluation of poly(ARTEMA) anticancer potential on breast cancer cells. First, we synthesized ARTEMA using esterification followed by its polymerization using the reversible addition-fragmentation chain transfer (RAFT) polymerization method. We evaluated its mechanism of action, focusing on two key pathways: temperature-triggered singlet oxygen generation and ferrous ions (Fe2+) release, both of which contribute to ferroptosis. Our results demonstrate that poly(ARTEMA) selectively generates singlet oxygen and Fe2+ due to the endoperoxide crosslinks, leading to cell death in breast cancer cells. We also investigated the anti-cancer potential of poly(ARTEMA) on breast cancer cells with and without a ferroptosis inhibitor. The IC50 values were 125 µM for the MCF-7 cancer cell line and 300 µM for the normal MCF-10 cell line, indicating enhanced toxicity toward cancer cell lines. These findings suggested that poly(ARTEMA) induces ferroptosis in cancer cells and may serve as a promising candidate for cancer therapy with minimal cytotoxicity. To the best of our knowledge, this report may be the first that successfully synthesized poly(ARTEMA) using ART, with its anticancer potential evaluation.

The development of resistance significantly reduces the efficacy of targeted therapies, such as sunitinib, in renal cell carcinoma (RCC) patients, emphasizing the need for novel therapeutic agents. Natural products, known for their diverse chemical structures and mechanisms of action, offer promising anti-tumor potential with favorable safety profiles and lower toxicity compared to synthetic drugs. 2-Undecanone, a natural compound extracted from Houttuynia cordata Thunb., has demonstrated anti-tumor effects, but its specific role in RCC treatment remains unclear. In this study, we integrated network pharmacology with in vitro experiments to explore the mechanisms underlying 2-Undecanone's effects on RCC. Our results reveal that 2-Undecanone effectively inhibits RCC cell viability, proliferation, and migration. Mechanistically, we discovered that 2-Undecanone induces ferroptosis in RCC cells by promoting reactive oxygen species (ROS) generation, intracellular Fe2+ accumulation, glutathione (GSH) production, lipid peroxidation, and modulation of the STAT3/GPX4 signaling pathway. Furthermore, 2-Undecanone lowers the IC50 value of sunitinib in RCC cells, enhancing their sensitivity to this targeted therapy. Additionally, 2-Undecanone potentiates sunitinib-induced ferroptosis. In summary, our research reveals that 2-Undecanone enhances the sensitivity of RCC cells to sunitinib through targeting the STAT3/GPX4 pathway, providing new insights into potential therapeutic strategies for RCC.

The incidence of cutaneous squamous cell carcinoma (CSCC) is increasing rapidly. This study discussed the effects of artesunate (ART) on CSCC cell proliferation and migration via the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) pathway. MTT assessed cell viability and analyzed the IC50 value (69.26 μM). Accordingly, human CSCC cells (A431) were cultured in vitro, and treated with 70 μM ART, Ferrostatin-1, oe-SLC7A11, and C646, with cell biological behavior assessed. The potential targets of ART were predicted. p53 acetylation and protein stability and ART-p300 binding were examined. Thymusless nude mice were subcutaneously inoculated with A431 cells, and treated with ART and C646. ART-treated A431 cells showed weakened proliferation, migration, lactate dehydrogenase levels, oxidized glutathione/glutathione ratio, reactive oxygen species, malondialdehyde, and active Fe2+ levels, which could be reversed by suppressing ferroptosis. ART promoted p53 acetylation and protein stability and curbed the SLC7A11-GPX4 pathway by targeting p300. ART stimulated ferroptosis via the SLC7A11-GPX4 pathway, thereby repressing CSCC cell proliferation and migration, which were counteracted by p300 inhibition. ART regulated the SLC7A11-GPX4 pathway by up-regulating the p300-p53 axis, thereby hindering tumor growth in vivo. Collectively, ART inhibits CSCC proliferation and migration by modulating the SLC7A11-GPX4 pathway through the p300-p53 axis.

Axitinib resistance remains a serious challenge in the treatment of advanced renal cell carcinoma (RCC), and the underlying mechanisms are not fully understood. Here, we constructed an in vivo axitinib-resistant RCC model and identified the long non-coding RNA STX17-DT as a driver of therapy resistance in RCC. The expression of STX17-DT was significantly elevated in axitinib-resistant RCC cells and correlated with poorer prognosis in RCC patients. Elevated levels of STX17-DT contributed to the development of resistance to axitinib both in vitro and in vivo. Mechanistically, STX17-DT modulated the stability of IFI6 mRNA by recruiting and binding to hnRNPA1, leading to decreased accumulation of mitochondrial reactive oxygen species (ROS) and attenuated ferroptosis. Meanwhile, STX17-DT was packaged into extracellular vesicles through hnRNPA1, thus transmitting axitinib resistance to other cells. Compared with axitinib monotherapy, combined treatment of axitinib and STX17-DT-targeted in vivo siRNA demonstrated enhanced therapeutic efficacy. These findings indicate a novel molecular mechanism of axitinib resistance in RCC and suggest that STX17-DT may serve as a prognostic indicator and potential therapeutic target to overcome resistance to targeted therapy.

Maintaining iron homeostasis is necessary for kidney functioning. There is more and more research indicating that kidney disease is often caused by iron imbalance. Over the past decade, ferroptosis' role in mediating the development and progression of renal disorders, such as acute kidney injury (renal ischemia-reperfusion injury, drug-induced acute kidney injury, severe acute pancreatitis induced acute kidney injury and sepsis-associated acute kidney injury), chronic kidney disease (diabetic nephropathy, renal fibrosis, autosomal dominant polycystic kidney disease) and renal cell carcinoma, has come into focus. Thus, knowing kidney iron metabolism and ferroptosis regulation may enhance disease therapy. In this review, we discuss the metabolic and molecular mechanisms of iron signaling and ferroptosis in kidney disease. We also explore the possible targets of ferroptosis in the therapy of renal illness, as well as their existing limitations and future strategies.

Lung cancer is a medical ailment with high mortality and prevalence rates. Artemisinin (ART) and its derivatives exhibit anti-cancer properties against various malignancies, including lung cancer. However, further research is required to determine the precise anti-cancer mechanisms of ART. Hence, this study aimed to utilize network pharmacology to preliminarily investigate the therapeutic effectiveness and mode of action of this medication.

Using a bioinformatics approach, five target proteins with the strongest connections were selected for docking. Gene enrichment analysis was performed, and the ART target proteins were predicted. Various methods, including methyl thiazolyl tetrazolium (MTT) assays, colony formation assays, microsphere formation assays, flow cytometry, and western blotting analysis, were employed to assess the impact of ART on the malignant characteristics of lung cancer cells.

Bioinformatic analysis identified 51 ART target genes in lung adenocarcinoma for further analysis. Pathway enrichment analysis of target genes revealed 639 enriched Gene Ontology-Biological Process (GO BP) and 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These findings imply that ART may control the IL-6 signaling pathway by focusing on important molecules such as CDK4 and IL-6. The ART-treated group experienced apoptosis induction, cell cycle arrest, and inhibition of cell proliferation and microsphere formation compared with the control group (p < 0.05, p < 0.01). Additionally, ART reduced the protein expression of CDK4, COX2, ERBB2, CD44, and EpCAM while increasing that of caspase 3, IL-6, p53, and SRC (p < 0.01).

ART inhibited the growth and stemness of HCC827 cells.

Protein arginine methyltransferases (PRMTs) play an essential role in the regulation of ferroptosis, a form of programmed cell death characterized by abnormal iron ion metabolism, lipid peroxidation, and DNA damage. Through methylation, PRMTs modify specific proteins, thereby altering their activity, localizations, or interactions with other molecules to control the ferroptosis process. This study was conducted to provide a comprehensive overview of the relationship between PRMTs and ferroptosis, with a focus on the mechanisms by which PRMTs regulate ferroptosis and their effect on this cell death pathway. Currently, only a few studies have been conducted on the regulation of ferroptosis by PRMTs. However, this review provides insights into the effects of PRMTs on ferroptosis regulators, suggesting that the regulation of ferroptosis by PRMTs holds potential as a new therapeutic target for related diseases.

The dysregulation of ribosome biogenesis has been extensively identified in various cancers, making it emerge as a hallmark of malignant cells. This highlights the potential of targeting ribosome biogenesis as an effective approach for treating cancer patients. Although chemotherapy drugs including doxorubicin and cisplatin often target ribosome biogenesis to induce DNA damage or inhibit tumor cell proliferation, they are associated with significant side effects.

This study aims to reveal the novel role of artesunate (ART), a well-known antimalarial drug, in suppressing ribosome RNA biogenesis in ovarian cancer.

In this study, the inhibitory effects of ART on ovarian cancer were studied both in vitro and in vivo. The effects of ART on ribosome RNA biogenesis were detected by 5-ethynyl uridine staining, RT-qPCR, and western blotting. Drug affinity responsive target stability, mass spectrometry, molecular docking and western blotting were combined to identify ART molecular targets.

Ovarian cancer cells treated with ART exhibited significant reduction in nascent rRNA synthesis, accompanied by a remarkable down-regulation of pre-rRNA and mature rRNA expression. The inhibitory effect of ART on ribosome biogenesis subsequently impaired cell proliferation, cell migration and invasion, and induced apoptosis. In eukaryotes, ribosome RNA synthesis primarily occurs in the nucleus, involving processes such as rDNA transcription, pre-rRNA splicing and the assembly of ribosome precursors with ribosomal proteins, other closely-related proteins and small nucleolar RNAs. We observed that ART inhibited the nuclear translocation of FANCA through binding to FANCA protein, consequently leading to the inhibition of ribosome RNA synthesis. Moreover, knockdown of FANCA in ovarian tumor cells resulted in reduced rRNA transcription, suppressed cell proliferation and migration, and induced apoptosis which might be mediated through the inhibition of mTOR/RPS6 activity. In vivo studies using xenograft tumors in nude mice demonstrated that ART repressed the growth of established ovarian cancer tumors. Additionally, ART treatment significantly altered FANCA protein level in these tumors, especially suppressed its nuclear localization.

These findings establish ART as a potent inhibitor of ribosome biogenesis, presenting a promising therapeutic avenue for ovarian tumors with high FANCA expression or for cancer patients exhibiting abnormal activation of the mTOR-RPS6 pathway.

Renal cell carcinoma (RCC) is one of the most diagnosed urological malignancies with high mortality and increasing incidence. What's more, the sunitinib resistance undoubtedly increased the difficulties in RCC therapy. Circular RNAs (circRNAs) are a newly found type of non-coding RNAs with a special circular structure, and are found to participate in the occurrence development, chemoresistance, and prognosis of cancers. Ferroptosis regulates disease progression mainly via polyunsaturated fatty acid metabolism and glutamine catabolic pathways. The mechanism of circRNAs contributed to sunitinib resistance through ferroptosis has not been elucidated clearly.

In our research, we identified a novel circRNA Hsa_circ_0072732 from circRNA datasets (GSE108735 and GSE100186). RNase R and Actinomycin D assays were used to detect the loop structure and stability of circRNAs. qRT-PCR and western blot were used for the detection of RNA and protein levels. CCK8 assays were used to detect proliferation and cell viability. Lipid peroxidation (MDA), and reactive oxygen species (ROS) were detected by indicted kits. Dual-luciferase reporter and RNA pull-down assays were used to detect the RNA interactions.

Our results showed that Hsa_circ_0072732 was highly expressed in RCC cells. Further investigations showed that the silence of Hsa_circ_0072732 could increase RCC sensitivity to sunitinib. Hsa_circ_0072732 contributed to sunitinib chemoresistance by impairing ferroptosis. Hsa_circ_0072732 exerts its function mainly by acting as sponges for miR-548b-3p and regulating the expression SLC7A11. Our research suggests that ferroptosis is involved in sunitinib resistance, and targeting ferroptosis is a promising way for RCC treatment.

Our research suggests Hsa_circ_0072732 enhanced renal cell carcinoma sunitinib resistance by inhibiting ferroptosis through miR-548b-3p/SLC7A11.

This study aimed to investigate the prognostic value of miRNAs and ferroptosis-related genes in cervical squamous cell carcinoma.

We mined data from public databases for differentially expressed miRNAs, ferroptosis-related genes, and clinical parameters and constructed a prognostic risk model. The predictive performance of the model was evaluated using survival and receiver operating characteristic curve analyses. We combined the clinicopathological features to construct a nomogram and evaluated its efficacy using calibration and clinical decision curves. The correlation between miRNA characteristics, risk score, and the tumor microenvironment was also studied. Next, consensus and key genes were screened, and their biological functions were analyzed using KEGG, GO, GSEA, and drug sensitivity analysis. Finally, the expression of miRNAs and key genes was detected using qRT-PCR and western blotting to verify the prediction results.

Seven miRNA signatures (miR-100-3p, miR-301a-5p, miR-331-3p, miR-425-5p, miR-502-3p, miR-505-5p, and miR-629-3p) were generated, and prognostic risk and nomogram models were successfully constructed. These models exhibited good accuracy. miRNA signatures correlated with the tumor microenvironment. Twelve consensus genes and three key genes (SLC2A1, ANO6, and TXNIP) were screened and their biofunctional diversity was identified using various analytical methods. qRT-PCR and western blotting were used to verify the expression of miR-301a-5p, miR-505-5p, SLC2A1, and TXNIP in cervical squamous carcinoma. The results were consistent with those of bioinformatics analyses.

Seven miRNAs may serve as prognostic biomarkers of cervical squamous cell carcinoma. SLC2A1, ANO6, and TXNIP are associated with cervical squamous cell carcinoma and may serve as ferroptosis-related markers of the disease.

Artesunate (ART) is a classic antimalarial drug with high efficiency, low toxicity and tolerance. It has been shown to be safe and has good anti-tumor effect. Existing clinical studies have shown that the anti-tumor mechanisms of ART mainly include inducing apoptosis and autophagy of tumor cells, affecting tumor microenvironment, regulating immune response, overcoming drug resistance, as well as inhibiting tumor cell proliferation, migration, invasion, and angiogenesis. ART has been proven to fight against lung cancer, hepatocarcinoma, lymphoma, multiple myeloma, leukemia, colorectal cancer, ovarian cancer, cervical cancer, malignant melanoma, oral squamous cell carcinoma, bladder cancer, prostate cancer and other neoplasms. In this review, we highlight the effects of ART on various tumors with an emphasis on its anti-tumor mechanism, which is helpful to propose the potential research directions of ART and expand its clinical application.

Equol is an isoflavone-derived metabolite known to exhibit strong estrogenic and antioxidant activities. The aim of this paper is twofold: first, to confirm the anticancer potential of equol against colorectal cancer, and second, to reveal the underlying mechanisms. After treatment with 40 μg/mL equol, cell proliferation, cell migration, and colony formation of HCT116 colon cancer cells were inhibited. Network pharmacology and transcriptomics analysis revealed the downregulation of genes related to DNA replication (CCND1, E2F1, CDC6, CDC45, MCM4), leading to G1/S cell cycle arrest and the induction of cell apoptosis, which was confirmed by flow cytometry. Genes associated with the G2-to-M transition (CDK1, CCNA2, CCNB1) were also downregulated. In addition, equol downregulated genes (FOXM1 and ASPM) that control cell migration and invasion. Our data indicate that equol can inhibit colorectal cancer by targeting multiple pathways, suggesting its potential as a key component in the adjuvant treatment of colorectal cancer.

In recent years, ferroptosis has gradually attracted increasing attention because of its important role in tumors. Ferroptosis resistance is an important cause of tumor metastasis, recurrence and drug resistance. Exploring the initiating factors and specific mechanisms of ferroptosis has become a key strategy to block tumor progression and improve drug sensitivity. As the external space in direct contact with tumor cells, the tumor microenvironment has a great impact on the biological function of tumor cells. The relationships between abnormal environmental characteristics (hypoxia, lactic acid accumulation, etc.) in the microenvironment and ferroptosis of tumor cells has not been fully characterized. This review focuses on the characteristics of the tumor microenvironment and summarizes the mechanisms of ferroptosis under different environmental factors, aiming to provide new insights for subsequent targeted therapy. Moreover, considering the presence of anticancer drugs in the microenvironment, we further summarize the mechanisms of ferroptosis to provide new strategies for the sensitization of tumor cells to drugs.

As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxia-inducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHL-deficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis.

Renal cancer is a common and serious malignant tumor of the urinary system. While surgery effectively treats early-stage renal cancer, advanced cases pose a significant challenge due to poor treatment outcomes and chemotherapy resistance. Therefore, there is an urgent need to develop alternative therapeutic strategies. Ferroptosis is a newly defined form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, which plays a critical role in tumor progression and drug resistance. Recent studies have shown that ferroptosis is involved in the occurrence and development of renal cancer, and ferroptosis-related genes can induce cell apoptosis and can be used as potential biomarkers for early diagnosis of renal cancer and participate in drug resistance of renal cancer chemotherapy. With the continuous improvement of the mechanism of ferroptosis, drugs targeting ferroptosis for the treatment of renal cancer are emerging in an endless stream. Based on the theoretical basis of the occurrence of ferroptosis, this paper reviewed drug-induced ferroptosis in renal cancer cells from the aspects of herbal medicine, natural compounds, drug resistance mechanisms, and nanomaterials, and delves into the clinical application potential of ferroptosis-related drugs in the treatment of renal cancer.

Redox imbalance is reported to play a pivotal role in tumorigenesis, cancer development, and drug resistance. Severe oxidative damage is a general consequence of cancer cell responses to treatment and may cause cancer cell death or severe adverse effects. To maintain their longevity, cancer cells can rescue redox balance and enter a state of resistance to anticancer drugs. Therefore, targeting redox signalling pathways has emerged as an attractive and prospective strategy for enhancing the efficacy of anticancer drugs and decreasing their adverse effects. Over the past few decades, natural products (NPs) have become an invaluable source for developing new anticancer drugs due to their high efficacy and low toxicity. Increasing evidence has demonstrated that many NPs exhibit remarkable antitumour effects, whether used alone or as adjuvants, and are emerging as effective approaches to enhance sensitivity and decrease the adverse effects of conventional cancer therapies by regulating redox balance. Among them are several novel anticancer drugs based on NPs that have entered clinical trials. In this review, we summarize the synergistic anticancer effects and related redox mechanisms of the combination of NPs with conventional anticancer drugs. We believe that NPs targeting redox regulation will represent promising novel candidates and provide prospects for cancer treatment in the future.

Artemisinin is a natural sesquiterpene lactone obtained from the traditional Chinese medicinal herb Artemisia annua L. (qinghao). Artemisinin and its derivatives share an unusual endoperoxide bridge and are extensively used for malaria treatment worldwide. In addition to antimalarial activities, artemisinin and its derivatives have been reported to exhibit promising anticancer effects in recent decades. In this review, we focused on the research progress of artemisinin and its derivatives with potential anticancer activities. The pharmacological effects, potential mechanisms, and clinical trials in cancer therapy of artemisinin and its derivatives were discussed. This review may facilitate the future exploration of artemisinin and its derivatives as effective anticancer agents.

Cancer is a major disease with ever-increasing morbidity and mortality. The metabolites derived from traditional Chinese medicine (TCM) have played a significant role in combating cancers with curative efficacy and unique advantages. Ferroptosis, an iron-dependent programmed death characterized by the accumulation of lipid peroxide, stands out from the conventional forms of cell death, such as apoptosis, pyroptosis, necrosis, and autophagy. Recent evidence has demonstrated the potential of TCM metabolites targeting ferroptosis for cancer therapy. We collected and screened related articles published in or before June 2023 using PubMed, Google Scholar, and Web of Science. The searched keywords in scientific databases were ferroptosis, cancer, tumor, traditional Chinese medicine, botanical drugs, and phytomedicine. Only research related to ferroptosis, the metabolites from TCM, and cancer was considered. In this review, we introduce an overview of the current knowledge regarding the ferroptosis mechanisms and review the research advances on the metabolites of TCM inhibiting cancer by targeting ferroptosis.

Ferroptosis is a form of non-apoptotic regulated cell death (RCD) that depends on iron and is characterized by the accumulation of lipid peroxides to lethal levels. Ferroptosis involves multiple pathways including redox balance, iron regulation, mitochondrial function, and amino acid, lipid, and glycometabolism. Furthermore, various disease-related signaling pathways also play a role in regulating the process of iron oxidation. In recent years, with the emergence of the concept of ferroptosis and the in-depth study of its mechanisms, ferroptosis is closely associated with various biological conditions related to kidney diseases, including kidney organ development, aging, immunity, and cancer. This article reviews the development of the concept of ferroptosis, the mechanisms of ferroptosis (including GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, GCH1-BH4, and MBOAT1/2 pathways), and the latest research progress on its involvement in kidney diseases. It summarizes research on ferroptosis in kidney diseases within the frameworks of metabolism, reactive oxygen biology, and iron biology. The article introduces key regulatory factors and mechanisms of ferroptosis in kidney diseases, as well as important concepts and major open questions in ferroptosis and related natural compounds. It is hoped that in future research, further breakthroughs can be made in understanding the regulation mechanism of ferroptosis and utilizing ferroptosis to promote treatments for kidney diseases, such as acute kidney injury(AKI), chronic kidney disease (CKD), diabetic nephropathy(DN), and renal cell carcinoma. This paves the way for a new approach to research, prevent, and treat clinical kidney diseases.

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.

The development of resistance to tyrosine kinase inhibitors (TKIs) is a major cause of treatment failure in metastatic renal cell carcinoma (mRCC). A deeper understanding of the metabolic mechanisms associated with TKI resistance is critical for refining therapeutic strategies. In this study, we established resistance to sunitinib and pazopanib by exposing a parental Caki-1 cell line to increasing concentrations of sunitinib and pazopanib. The intracellular and extracellular metabolome of sunitinib- and pazopanib-resistant mRCC cells were investigated using a nuclear magnetic resonance (NMR)-based metabolomics approach. Data analysis included multivariate and univariate methods, as well as pathway and network analyses. Distinct metabolic signatures in sunitinib- and pazopanib-resistant RCC cells were found for the first time in this study. A common metabolic reprogramming pattern was observed in amino acid, glycerophospholipid, and nicotinate and nicotinamide metabolism. Sunitinib-resistant cells exhibited marked alterations in metabolites involved in antioxidant defence mechanisms, while pazopanib-resistant cells showed alterations in metabolites associated with energy pathways. Sunitinib-resistant RCC cells demonstrated an increased ability to proliferate, whereas pazopanib-resistant cells appeared to restructure their energy metabolism and undergo alterations in pathways associated with cell death. These findings provide potential targets for novel therapeutic strategies to overcome TKI resistance in mRCC through metabolic regulation.

Ferroptosis is an iron-dependent cell death form that initiates lipid peroxidation (LPO) in tumors. In recent years, there has been growing interest on ferroptosis, but how to propel it forward translational medicine remains in mist. Although experimental ferroptosis inducers such as RSL3 and erastin have demonstrated bioactivity in vitro, the poor antitumor outcome in animal model limits their development. In this study, we reveal a novel ferroptosis inducer, oxaliplatin-artesunate (OART), which exhibits substantial bioactivity in vitro and vivo, and we verify its feasibility in cancer immunotherapy. For mechanism, OART induces cytoplasmic and mitochondrial LPO to promote tumor ferroptosis, via inhibiting glutathione-mediated ferroptosis defense system, enhancing iron-dependent Fenton reaction, and initiating mitochondrial LPO. The destroyed mitochondrial membrane potential, disturbed mitochondrial fusion and fission, as well as downregulation of dihydroorotate dehydrogenase mutually contribute to mitochondrial LPO. Consequently, OART enhances tumor immunogenicity by releasing damage associated molecular patterns and promoting antigen presenting cells maturation, thereby transforming tumor environment from immunosuppressive to immunosensitive. By establishing in vivo model of tumorigenesis and lung metastasis, we verified that OART improves the systematic immune response. In summary, OART has enormous clinical potential for ferroptosis-based cancer therapy in translational medicine.

Ferroptosis, a newly recognized form of programmed cell death, is distinguished by its reliance on reactive oxygen species and iron-mediated lipid peroxidation, setting it apart from established types like apoptosis, cell necrosis, and autophagy. Recent studies suggest its role in exacerbating or mitigating diseases by influencing metabolic and signaling pathways in conditions such as tumors and ischemic organ damage. Evidence also links ferroptosis to various kidney diseases, prompting a review of its research status and potential breakthroughs in understanding and treating these conditions.

In acute kidney disease (AKI), ferroptosis has been confirmed in animal kidneys after being induced by various factors such as renal ischemia-reperfusion and cisplatin, and glutathione peroxidase 4 (GPX4) is linked with AKI. Ferroptosis is associated with renal fibrosis in chronic kidney disease (CKD), TGF-β1 being crucial in this regard. In diabetic nephropathy (DN), high SLC7A11 and low nuclear receptor coactivator 4 (NCOA4) expressions are linked to disease progression. For polycystic kidney disease (PKD), ferroptosis promotes the disease by regulating ferroptosis in kidney tissue. Renal cell carcinoma (RCC) and lupus nephritis (LN) also have links to ferroptosis, with mtDNA and iron accumulation causing RCC and oxidative stress causing LN.

Ferroptosis is a newly identified form of programmed cell death that is associated with various diseases. It targets metabolic and signaling pathways and has been linked to kidney diseases such as AKI, CKD, PKD, DN, LN, and clear cell RCC. Understanding its role in these diseases could lead to breakthroughs in their pathogenesis, etiology, and treatment.

This study aimed to explore the effect of CD276 expression on the sunitinib sensitivity of clear cell renal cell carcinoma (ccRCC) cell and animal models and the potential mechanisms involved.

CD276 expression levels of ccRCC and normal samples were analyzed via online databases and real-time quantitative PCR (RT-qPCR). CD276 was knocked down in ccRCC cell models (sunitinib-resistant 786-O/R cells and sunitinib-sensitive 786-O cells) using shRNA transfection, and the cells were exposed to a sunitinib (2 µM) environment. Cells proliferation was then analyzed using MTT assay and colony formation experiment. Alkaline comet assay, immunofluorescent staining, and western blot experiments were conducted to assess the DNA damage repair ability of the cells. Western blot was also used to observe the activation of FAK-MAPK pathway within the cells. Finally, a nude mouse xenograft model was established and the nude mice were orally administered sunitinib (40 mg/kg/d) to evaluate the in vivo effects of CD276 knockdown on the therapeutic efficacy of sunitinib against ccRCC.

CD276 was significantly upregulated in both ccRCC clinical tissue samples and cell models. In vitro experiments showed that knocking down CD276 reduced the survival rate, IC50 value, and colony-forming ability of ccRCC cells. Knocking down CD276 increased the comet tail moment (TM) values and γH2AX foci number, and reduced BRCA1 and RAD51 protein levels. Knocking down CD276 also decreased the levels of p-FAK, p-MEK, and p-ERK proteins.

Knocking down CD276 effectively improved the sensitivity of ccRCC cell and animal models to sunitinib treatment.

In recent years, due to advancements in medical conditions and the development of scientific research, the fundamental research of TCM antitumor treatments has progressed from the cellular level to the molecular and genetic levels. Previous studies have demonstrated the significant role of traditional Chinese medicine (TCM) in antitumor therapy through various mechanisms and pathways. Its mechanism of action is closely associated with cancer biology across different stages. This includes inhibiting tumor cell proliferation, blocking invasion and metastasis to surrounding tissues, inducing tumor cell apoptosis, inhibiting tumor angiogenesis, regulating immune function, maintaining genome stability, preventing mutation, and regulating cell energy metabolism. The use of TCM for eliciting antitumor effects not only has a good therapeutic effect and low side effects, it also provides a solid theoretical basis for clinical treatment and medication. This paper reviews the mechanism of the antitumor effects of TCM based on tumor characteristics. Through our review, we found that TCM not only directly inhibits tumors, but also enhances the body's immunity, thereby indirectly inducing an antitumor effect. This function aligns with the TCM theory of "strengthening the body's resistance to eliminate pathogenic factors". Furthermore, TCM will play a significant role in tumor treatment in clinical settings.

Ferroptosis is caused by the accumulation of cellular reactive oxygen species that exceed the antioxidant load that glutathione (GSH) and phospholipid hydroperoxidases with GSH-based substrates can carry When the antioxidant capacity of cells is reduced, lipid reactive oxygen species accumulate, which can cause oxidative death. Ferroptosis, an iron-dependent regulatory necrosis pathway, has emerged as a new modality of cell death that is strongly associated with cancer. Surgery, chemotherapy and radiotherapy are the main methods of cancer treatment. However, resistance to these mainstream anticancer drugs and strong toxic side effects have forced the development of alternative treatments with high efficiency and low toxicity. In recent years, an increasing number of studies have shown that traditional Chinese medicines (TCMs), especially herbs or herbal extracts, can inhibit tumor cell growth and metastasis by inducing ferroptosis, suggesting that they could be promising agents for cancer treatment. This article reviews the current research progress on the antitumor effects of TCMs through the induction of ferroptosis. The aim of these studies was to elucidate the potential mechanisms of targeting ferroptosis in cancer, and the findings could lead to new directions and reference values for developing better cancer treatment strategies.

Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically with age, and the overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective in older individuals. Conventional cancer treatments, such as radiotherapy, surgery, and chemotherapy, have been used for decades to combat cancer. However, the emergence of novel fields of cancer research has led to the exploration of innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted therapy, multi-omics, and also multi-target therapy. The hypothesis was based on that drugs designed to act against individual targets cannot usually battle multigenic diseases like cancer. Multi-target therapies, either in combination or sequential order, have been recommended to combat acquired and intrinsic resistance to anti-cancer treatments. Several studies focused on multi-targeting treatments due to their advantages include; overcoming clonal heterogeneity, lower risk of multi-drug resistance (MDR), decreased drug toxicity, and thereby lower side effects. In this study, we'll discuss about multi-target drugs, their benefits in improving cancer treatments, and recent advances in the field of multi-targeted drugs. Also, we will study the research that performed clinical trials using multi-target therapeutic agents for cancer treatment.

While pachymic acid (PA), a key component of Poria cocos (Schw.), has demonstrated anti-tumor effects in lung, breast, and pancreatic cancers, its impact on renal cell carcinoma (RCC) is unclear. This study evaluated the effect of PA on proliferation, migration, and apoptosis in human renal cancer A498 and ACHN cells as well as in cancer xenograft mice using wound scratch test, Western blotting, and co-immunoprecipitation assays. In a dose- and time-dependent manner, PA exhibited significant inhibition of RCC cell proliferation, migration, and invasion, accompanied by the induction of apoptosis. Additionally, PA upregulated the expression of tumor protein p53-inducible nuclear protein 2 (TP53INP2) and tumor necrosis factor receptor-associated factor 6 (TRAF6), which were downregulated in renal papillary and chromophobe carcinoma, resulting in inhibited tumor growth in mice. PA treatment elevated cleaved-caspase 3 and 8, and PARP levels, and facilitated TP53INP2 and TRAF6 binding to caspase 8, promoting its ubiquitination. Molecular docking revealed interactions between PA and TP53INP2, TRAF6. In summary, PA inhibits RCC development by upregulating TP53INP2 and promoting TRAF6-induced caspase 8 ubiquitination, activating apoptotic pathways.

Ferroptosis, a novel form of regulated cell death characterized by dependence on iron and lipid peroxidation, has been implicated in a wide range of clinical conditions including neurological diseases, cardiovascular disorders, acute kidney failure, and various types of cancer. Therefore, it is critical to suppress cancer progression and proliferation. Ferroptosis can be triggered in cancer cells and some normal cells by synthetic substances, such as erastin, Ras-selective lethal small molecule-3, or clinical pharmaceuticals. Natural bioactive compounds are traditional drug discovery tools, and some have been therapeutically used as dietary additives or pharmaceutical agents against various malignancies. The fact that natural products have multiple targets and minimal side effects has led to notable advances in anticancer research. Research has indicated that ferroptosis can also be induced by natural compounds during cancer treatment. In this review, we focused on the most recent developments in emerging molecular processes and the significance of ferroptosis in cancer. To provide new perspectives on the future development of ferroptosis-related anticancer medications, we also provide a summary of the implications of natural phytochemicals in triggering ferroptosis through ROS production and ferritinophagy induction in a variety of malignancies.

Ferroptosis plays an important role in enhancing the efficacy of anti-programmed cell death 1 (PD-1) immunotherapy; however, the molecular mechanisms by which tumor ferroptosis sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy have not been elucidated.

Cytotoxicity assays, colony formation assays, flow cytometry and animal experiments were used to evaluate the effects of mefloquine (Mef) on survival and ferroptosis in melanoma and lung cancer. RNA sequencing, Real-time quantitative PCR (qRT-PCR), western blotting, chromatin immunoprecipitation-qPCR and flow cytometry were used to determine the molecular mechanisms by which Mef regulates lysophosphatidylcholine acyltransferase 3 (LPCAT3). The relationship between LPCAT3 and the efficacy of anti-PD-1 immunotherapy was verified via a clinical database and single-cell RNA sequencing (ScRNA-Seq).

In this study, we discovered that Mef induces ferroptosis. Furthermore, treatment with Mef in combination with T-cell-derived interferon-γ (IFN-γ) enhanced tumor ferroptosis and sensitized melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef upregulated the expression of LPCAT3, a key gene involved in lipid peroxidation, by activating IFN-γ-induced STAT1-IRF1 signaling, and knocking down LPCAT3 impaired the induction of ferroptosis by Mef+IFN-γ. Clinically, analysis of the transcriptome and single-cell sequencing results in patients with melanoma showed that LPCAT3 expression was significantly lower in patients with melanoma than in control individuals, and LPCAT3 expression was positively correlated with the efficacy of anti-PD-1 immunotherapy.

In conclusion, our study demonstrated a novel mechanism by which LPCAT3 is regulated, and demonstrated that Mef is a highly promising new target that can be utilized to enhance the efficacy of anti-PD-1 immunotherapy.

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation of iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in the biological processes of tumors. Intriguingly, mesenchymal and dedifferentiated cancer cells, which are usually resistant to apoptosis and traditional therapies, are exquisitely vulnerable to ferroptosis, further underscoring its potential as a treatment approach for cancers, especially for refractory cancers. However, the impact of ferroptosis on cancer extends beyond its direct cytotoxic effect on tumor cells. Ferroptosis induction not only inhibits cancer but also promotes cancer development due to its potential negative impact on anticancer immunity. Thus, a comprehensive understanding of the role of ferroptosis in cancer is crucial for the successful translation of ferroptosis therapy from the laboratory to clinical applications. In this review, we provide an overview of the recent advancements in understanding ferroptosis in cancer, covering molecular mechanisms, biological functions, regulatory pathways, and interactions with the tumor microenvironment. We also summarize the potential applications of ferroptosis induction in immunotherapy, radiotherapy, and systemic therapy, as well as ferroptosis inhibition for cancer treatment in various conditions. We finally discuss ferroptosis markers, the current challenges and future directions of ferroptosis in the treatment of cancer.

Various treatment options, such as molecular targeted drugs and immune checkpoint blockades, are available for patients with cancer. However, some cancer types are refractory to molecular targeted therapies or acquire drug resistance after long-term treatment. Thus, ferroptosis, a newly defined type of programmed cell death caused by the iron-dependent accumulation of lipid peroxidation, has gained attention as a novel cancer treatment strategy. Understanding cell-cell interactions in the tumor microenvironment is important for the clinical application of ferroptosis inducers. However, the effects of cell-cell interactions on ferroptosis sensitivity remain unclear. Thus, we aimed to evaluate the effects of macrophage-cancer cell interactions on ferroptosis induction. Coculture experiments showed that conditioned medium prepared from macrophages did not alter the ferroptosis sensitivity of cancer cells. By contrast, coculture via transwell, which enables cell-cell interactions through secretion, increased the sensitivity of cancer cells to ferroptosis inducers. Additionally, direct coculture increased the susceptibility of cancer cells to RSL3-induced ferroptosis. Mechanistically, coculture with macrophages upregulated the levels of intracellular ferrous ions and lipid peroxidation in cancer cells. These findings provide novel insights into the mechanisms by which cell-cell interactions influence ferroptosis induction and application of ferroptosis inducers as a cancer treatment option.

Imatinib has become an exceptionally effective targeted drug for treating gastrointestinal stromal tumors (GISTs). Despite its efficacy, the resistance to imatinib is common in GIST patients, posing a significant challenge to the effective treatment.

The expression profiling of TRIM21, USP15, and ACSL4 in GIST patients was evaluated using Western blot and immunohistochemistry. To silence gene expression, shRNA was utilized. Biological function of TRIM21, USP15, and ACSL4 was examined through various methods, including resistance index calculation, colony formation, shRNA interference, and xenograft mouse model. The molecular mechanism of TRIM21 and USP15 in GIST was determined by conducting Western blot, co-immunoprecipitation, and quantitative real-time PCR (qPCR) analyses.

Here we demonstrated that downregulation of ACSL4 is associated with imatinib (IM) resistance in GIST. Moreover, clinical data showed that higher levels of ACSL4 expression are positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that the reduced expression of ACSL4 in GIST is attributed to excessive protein degradation mediated by the E3 ligase TRIM21 and the deubiquitinase USP15.

These findings demonstrate that the TRIM21 and USP15 control ACSL4 stability to maintain the IM sensitive/resistant status of GIST.