PMCID string | Title string | Sentences string |
|---|---|---|
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | GIST‐T1‐IR cell lysates were incubated with either biotin or β‐elemene‐biotin at 4°C overnight, and then a pulldown assay was performed. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | GIST‐T1‐IR cell lysates were preincubated with either DMSO or free β‐elemene, followed by subsequent incubation with β‐elemene‐biotin. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | The interaction between N6AMT1 and β‐elemene was then detected by capturing β‐elemene‐biotin. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | The mutant N6AMT1 proteins were incubated with β‐elemene, followed by protein affinity pull‐down assay and detected by immunoblotting. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Western blot analysis of N6AMT1/NRF2/HMOX1 axis in GIST cells treated with imatinib, β‐elemene or imatinib+β‐elemene. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Western blot analysis of NRF2 in cytosol protein and nuclear protein. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | The staining intensity and localisation of NRF2 in the indicated groups were analysed by immunofluorescence staining. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Western blot analysis of the relationship of NRF2 and HMOX1 in ferroptosis with knockdown of NRF2 in GIST cells followed by imatinib+β‐elemene treatment. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Methylation level of NRF2 promoter in GIST‐T1‐IR cell treated with imatinib, β‐elemene or imatinib+β‐elemene. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Methylation level of NRF2 promoter in GIST‐T1‐IR cell with or without N6AMT1 knockdown by siRNA. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Methylation level of NRF2 promoter in GIST‐T1‐IR cell with or without N6AMT1 overexpression. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Data represent the mean ± SD; *p < .05; **p < .01; ***p < .001. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | An unpaired t‐test was used unless otherwise stated. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Epigenetic modifications have been reported to play a critical role in the regulation of ferroptosis. , |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Moreover, β‐elemene can reverse gefitinib resistance in non‐small cell lung cancer through m6A methylation modification‐mediated autophagy. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Based on these previous studies, we speculate that β‐elemene may regulate the process of ferroptosis through epigenetic regulation. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Among these 53 potential target proteins, two epigenetic modifications related protein N6AMT1 and SMYD2 have been identified (Figure 6C,D). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | In particular, there was no correlation between SMYD2 knockout and HMOX1 expression (Figure S4A,B). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | The expression of HMOX1 is related to knockdown or overexpression of N6AMT1 (Figure 6E,F). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Therefore, we think that N6AMT1 may be a potential target of β‐elemene. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | We validated the interaction of β‐elemene with N6AMT1 in GIST‐882‐IR and GIST‐T1‐IR cells by the CETSA, and our result showed that β‐elemene significantly decreased the stability of N6AMT1 by promoting a thermal shift (Figure 6G). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Molecular docking was performed to provide deeper insight into the interactions between β‐elemene and N6AMT1. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Results showed that β‐elemene bound to N6AMT1 protein targets through visible hydrogen bonds and strong electrostatic interactions. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | To identify the binding site of β‐elemene, docking simulations were performed to model its interaction with each amino acid residue. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | As shown in Figures 6H and S5A,B, β‐elemene covalently bound to the N6AMT1 protein by contacts with scores of −6.68 kcal/mol for Asp103, −5.309 kcal/mol for Lys2 and −5.326 kcal/mol for Asn77. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | We synthesised β‐elemene‐biotin to determine the target of β‐elemene in GIST cells. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | The GIST‐T1‐IR cell lysates were subsequently treated with β‐elemene‐biotin and biotin. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Samples were analysed using an anti‐N6AMT1 antibody, verifying that β‐elemene precipitated N6AMT1. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Furthermore, preincubation with free β‐elemene inhibited the interaction between β‐elemene‐biotin and N6AMT1 (Figure 6I,J). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | We further examined the interactions between N6AMT1 and β‐elemene in this binding state by mutagenesis studies, followed by pull‐down assays. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | As illustrated in Figures 6K and S5C,D, mutations at Lys2 and Asn77 exerted a lesser impact, compared to mutations at Asp103. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | In conclusion, these findings indicated that β‐elemene covalently associates with N6AMT1, specifically targeting Asp103 of the protein. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | To evaluate whether N6AMT1 can affect the ferroptosis effect of β‐elemene, we initially knocked down N6AMT1 expression using a siRNA and N6AMT1 overexpression in GIST‐882‐IR and GIST‐T1‐IR cells (Figure S6A,E). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Knockdown of N6AMT1 resulted in a substantial reduction of cell viability in GIST‐882‐IR and GIST‐T1‐IR cells exposed to imatinib (Figure S6B). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Cell death assay revealed that N6AMT1 knockdown led to an increased level of PI‐positive cells (Figure S6C). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Moreover, the Fe levels were recorded to be increased after N6AMT1 knockdown (Figure S6D). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | However, when N6AMT1 was overexpressed in these cells, the inhibitory effect of β‐elemene combined with imatinib on cell viability and cell death assay was less pronounced (Figure S6F,G). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | The Fe levels were recorded to be increased after N6AMT1 overexpression (Figure S6H). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Collectively, these results suggest that N6AMT1 overexpression can reverse the inhibitory effects of β‐elemene combined with imatinib, and conversely N6AMT1 knockdown enhances the inhibitory effects of imatinib, indicating that N6AMT1 is the target of β‐elemene contributing to the ferroptosis effect. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | HMOX1 expression is mainly controlled by NRF2, a key transcription factor that promotes the transcription of HMOX1 to induce ferroptosis. , |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Thus, we monitored N6AMT1, NRF2 and HMOX1 levels in GIST cells exposed to the indicated drugs. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | As shown in Figure 6L, western blot analysis showed that the NRF2 levels were highly increased in the GIST cells with β‐elemene treatment, compared to control and imatinib alone, accompanied by the upregulation of HMOX1. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Treatment with β‐elemene can increase NRF2 level in the nucleus, thus promoting HMOX1 expression (Figure 6M). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Meanwhile, immunofluorescence staining also showed an increase in overall fluorescence intensity and fluorescence intensity in the nucleus in the GIST cells with β‐elemene treatment, compared to control and imatinib alone (Figure 6N). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | These results indicated that the expression of HOMX1 was associated with NRF2. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | To demonstrate that the expression of HMOX1 is regulated by NRF2, we further knocked down NRF2 expression in GIST cells. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Transfection with NRF2 siRNA inhibited the expression of HMOX1 (Figure 6O) and reversed the ferroptosis induced by treatment with β‐elemene and imatinib (Figure S7A,B). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Therefore, it is feasible to show that the NRF2/HMOX1 pathway plays a critical role in β‐elemene‐mediated ferroptosis of GIST cells. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Next, we further investigate the mechanism involved in the regulation of HMOX1 by N6AMT1. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | We have found that β‐elemene can increase the expression of NRF2 and HOMX1, but N6AMT1 expression did not change in GIST‐882‐IR and GIST‐T1‐IR cells after β‐elemene treatment (Figure 6L) before. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Regarding the fact that N6AMT1 has been reported as a methyltransferase, it is conceivable that N6AMT1 participates in ferroptosis through DNA hypermethylation of a certain transcription factor. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Since β‐elemene treatment did not affect the expression level of N6AMT1, we speculate that since β‐elemene binds to N6AMT1, it may inhibit the binding of N6AMT1 to NRF2 promoter regions, thereby suppressing its transcriptional repression function. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Thus, we assumed that β‐elemene was involved in NRF2 promoter methylation by inhibiting N6AMT1 function. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | We then measured methylation levels of the NRF2 promoter in GIST cells treated with β‐elemene plus imatinib or alone. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | As anticipated, β‐elemene significantly reduced methylation of the NRF2 promoter and increased NRF2 gene expression in GIST cells (Figures 6P and S8A). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | In addition, inhibition of N6AMT1 by siRNA promoted the expression of NRF2 protein levels (Figure 6E) and reduced the methylation level of the NRF2 promoter (Figures 6Q and S8B). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Conversely, overexpression of N6AMT1 triggered methylation of the NRF2 promoter (Figures 6R and S8C) and inhibited NRF2 gene expression in GIST cells (Figure 6F). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | In addition, we found that β‐elemene treatment, interference and overexpression of N6AMT1 had no obvious change on HMOX1 promoter (Figure S8D–I). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | These results indicate that β‐elemene target N6AMT1‐mediated DNA methylation of NRF2 promoter is a crucial factor in the regulatory axis of NRF2 and HMOX1. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Collectively, these results suggest that β‐elemene may bind to N6AMT1 to disturb its activity and interaction with the effectors. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Last, preclinical evaluation of the effects of β‐elemene and imatinib treatment on imatinib resistance was carried out using animal models. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | We had evaluated the effect of β‐elemene and imatinib therapy in the CDX models before. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Since β‐elemene induced ferroptosis via the NRF2/HMOX1 axis, we investigated the relevant marker in vivo model samples. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Consistent with our proposed mechanism of study, β‐elemene and imatinib co‐treated tumours showed concomitant increases in NRF2, HMOX1 and 4‐HNE staining (Figure 7A–D). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | β‐elemene improves imatinib therapeutic efficiency in imatinib‐resistant GIST. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | A–D) IHC staining of Nrf2, HMOX1 and 4‐HNE in tumour tissues generated by GIST‐T1‐IR cells‐based xenograft in the indicated groups. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Scale bars, 50 µm. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Schematic description of the in vivo anticancer effect of combined treatment with imatinib and β‐elemene in the patient‐derived xenograft (PDX) model. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Photograph and comparison of tumour sizes of the PDX model in the indicated groups. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Growth curve of the PDX model in the indicated groups. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | The tumour weight of the PDX model in the indicated groups. ( |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | I–M) IHC staining of 4‐HNE and HMOX1 in tumour tissues generated by the PDX model in the indicated groups. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Scale bars, 50 µm. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Data represent the mean ± SD; *p < .05; **p < .01; ***p < .001. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | An unpaired t‐test was used unless otherwise stated. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Further, we established PDX models with better clinical relevance by using clinically imatinib‐resistant GIST tissues, followed by treatment with indicated drugs (Figure 7E). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Similar to our CDX model, there was no statistical difference in both tumour size and weight between the control and imatinib groups, whereas the tumour was dramatically downsized in the β‐elemene and imatinib combination group (Figures 7F–H and S9A,B). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Compared with the control or imatinib alone, imatinib combined with β‐elemene treatment increased HMOX1, NRF2 and 4‐HNE levels, along with a decrease in Ki‐67 expression (Figure 7J–M). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Collectively, these results suggest that β‐elemene synergistically enhances the antitumour effect of imatinib in GIST with imatinib resistance. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Imatinib resistance remains a thorny issue in the clinical setting of GIST. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Hence, elucidation of the molecular mechanisms of imatinib resistance and developing a potential therapy strategy is pivotal. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Many possible causes underlying imatinib resistance in GIST are widely acknowledged, including the emergence of secondary mutations in KIT kinase domains, unknown effects of gene polymorphisms, activation of alternative cell death pathways and so on. , , |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Our findings support the concept that ferroptosis plays an important role in imatinib resistance. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Using GSEA, we found that ferroptosis activity is suppressed in imatinib‐resistant GIST and targeting ferroptosis could be a potential therapeutic option for GIST to eliminate tumours. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | However, many ferroptosis agonists are not currently in clinical use in GIST, and some phytochemicals are ideal adjuvants for therapy, which may have the potential to reverse the imatinib‐resistance of GIST cells. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Here, we first showed that β‐elemene and imatinib synergistically induce ferroptosis in imatinib‐resistant GIST cells and validated this effect in various models. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Further research shows that β‐elemene induced ferroptosis by promotion of Fe accumulation and ROS to promote the antitumour effect. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Mechanistically, β‐elemene binds to N6AMT1, which may inhibit the binding of N6AMT1 to NRF2 promoter regions, thereby activating the NRF2/HMOX1 pathway to induce ferroptosis (Figure 8). |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Summary diagram of the mechanism that β‐elemene increased the sensitivity of GIST cells to imatinib. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | β‐elemene specifically targets N6AMT1, inhibiting its transcriptional repression function and activating the NRF2‐HMOX1 signalling pathway to induce ferroptosis. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Previous studies suggest that alterations to ferroptosis‐related signalling pathways may provide new insights into reversing treatment resistance. , , |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Therefore, drugs targeting ferroptosis in GIST cells hold promise as a prospective treatment strategy for patients with imatinib‐resistant GIST. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | In this study, we found the levels of Fe, ROS and lipid peroxidation were significantly elevated in cells treated with the combination of β‐elemene and imatinib. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Besides, combination treatment inhibits the viability of GIST cells and promotes the sensitivity of imatinib in imatinib‐resistant GIST cells. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Further, combination treatment‐mediated cell death was blocked by the ferroptosis inhibitor Fer‐1 (Figure 3D), indicating that β‐elemene synergy with imatinib effectively activates ferroptosis in imatinib‐resistant GIST cells. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Subsequent experiments revealed that cotreatment with β‐elemene and imatinib induced the expression of HMOX1 to activate ferroptosis in GIST cells. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | HMOX1, as a rate‐limiting enzyme in heme catabolism, can decompose heme into CO, Fe and biliverdin, which play dual roles in ferroptosis. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | Several reports have revealed that the role of the NRF2/HOMX1 axis in ferroptosis is controversial. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | On one hand, it antagonises ferroptosis by inhibiting oxidation, and on the other hand, highly induced HMOX1 can aggravate heme degradation and release large amounts of free Fe. |
PMC12390768 | β‐elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1 | The excessive production of Fe and ROS can promote ferroptosis. , , |
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