PMCID string | Title string | Sentences string |
|---|---|---|
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | n = 3 mice per group. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | G Immunohistochemical staining representative pictures of hematoxylin-eosin (HE), KIT, STUB1, GPX4, Ki-67, and 4-HNE in GIST cell xenograft tumor tissues of mice from vehicle (DMSO), IM, RSL3, and combination treatment groups. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Scale bar, 100 μm. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | DMSO dimethyl sulfoxide, IM Imatinib, RSL3 Ras-selective lethal small molecule 3, 4-HNE 4-hydroxy-2-nonenal. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Significance denoted by: ns not significant, *P < 0.05, **P < 0.01, and ***P < 0.001. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Based on the staining intensity of STUB1 and GPX4 (Fig. 7A), IHC analysis of 418 tissue microarray samples revealed that there was a significant inverse correlation between the expression of STUB1 and GPX4 in GIST (Fig. 7B). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Subsequently, correlations between STUB1 and GPX4 expression and clinicopathological features in the 418 patients with GIST were analyzed. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The results showed that STUB1 expression was correlated with tumor location (P < 0.001), mitotic index (P < 0.001), NIH risk grade (P = 0.001), and cell morphology (P = 0.047). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The expression of GPX4 was correlated with tumor location (P = 0.020), mitotic index (P = 0.019) and NIH risk grade (P = 0.005) (Table S4). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The survival and recurrence status were last updated in August 2022. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Among the 418 included patients, 397 patients (95.0%) were followed up completely and 21 were lost to follow-up. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The median follow-up period was 48 (0–86) months. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | At the last follow-up, recurrence occurred in 34 cases (8.1%) and death in 4 (1.0%) cases. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The overall 3- and 5-year recurrence-free survival(RFS) rate was 93.3% and 90.9% respectively. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Log-rank analysis revealed significantly longer RFS in patients with high expression of STUB1 (P = 0.034) and low expression of GPX4 (P = 0.004; Fig. 7C, D). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | but there was no significant difference in overall survival(OS) (Fig. S9).Fig. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | 7STUB1 and GPX4 are independent prognostic factors for gastrointestinal stromal tumor (GIST).A Immunohistochemical analysis for the STUB1 and GPX4 expression in GIST tissue microarrays (n = 418). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | B Scatter plot showing a negative correlation between the expression of STUB1 and GPX4 in GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | C Low STUB1 expression predicted poor recurrence-free survival (RFS) in GIST patients. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | D High GPX4 expression predicted poor RFS in GIST patients. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | E Nomogram for predicting the probability of recurrence in patients with GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | F Calibration plot of the nomogram. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Scale bar, 50 μm in A. A Immunohistochemical analysis for the STUB1 and GPX4 expression in GIST tissue microarrays (n = 418). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | B Scatter plot showing a negative correlation between the expression of STUB1 and GPX4 in GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | C Low STUB1 expression predicted poor recurrence-free survival (RFS) in GIST patients. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | D High GPX4 expression predicted poor RFS in GIST patients. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | E Nomogram for predicting the probability of recurrence in patients with GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | F Calibration plot of the nomogram. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Scale bar, 50 μm in A. Univariate Cox analysis indicated that RFS was correlated with mitotic index (P < 0.001), cell morphology (P < 0.001), STUB1 expression (P = 0.039), and GPX4 expression (P = 0.006) (Table S5). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The results of multivariate Cox analysis showed that mitotic index > 5/50HPF (HR: 3.907, 95%CI: 1.838–8.305, P < 0.001), epithelial and mixed cell type (HR: 2.179, 95%CI: 1.013–4.685, P = 0.046) and high GPX4 expression (HR: 5.806, 95%CI: 2.349–14.353, P < 0.001) were independent risk factors for recurrence (Table S5). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The high expression of STUB1 (HR: 0.370, 95%CI: 0.172–0.794, P = 0.011) was an independent protective factor affecting the RFS of GIST patients. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | However, there was no correlation between OS and various factors (Table S6). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Multivariate analysis was used to create a nomogram for survival prediction, and it was observed that compared to other clinical variables, STUB1 and GPX4 expression had a significant impact on RFS (Fig. 7E). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The calibration plot showed good consistency between predicted and observed values, as the deviation correction line closely matched the ideal curve (45-degree line) (Fig. 7F). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | In summary, a valuable model for predicting recurrence in patients with GIST has been constructed. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The emergence of TKIs has improved the prognosis of GIST patients, however, approximately half of the patients develop acquired drug resistance due to secondary gene mutations within 2 years of treatment, which hinders the effectiveness of TKI treatment . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Therefore, exploring new treatment strategies is imperative. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Ferroptosis, a novel form of cell death has garnered significant attention . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Eliminating tumors by targeting ferroptosis could be a potential therapeutic option for GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | However, the role of ferroptosis in the tumorigenesis and progression of GIST and whether IM can induce ferroptosis remain unclear. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | In this study, we first detected the presence of ferroptosis in GIST-T1 and GIST-882 cells and found that inhibition of ferroptosis by Ferrostatin-1 partially reversed the effect of IM on GIST, indicating that ferroptosis does exist in GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The detection indexes of ferroptosis include the changes in mitochondrial morphology and levels of lipid ROS, Fe, and GSH . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | We observed a reduction in mitochondrial volume and an increase in mitochondrial crests in GIST cells treated with IM. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | IM increased ROS and lipid ROS levels in GIST cells, and this effect could be reversed by Ferrostatin-1. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | In addition, IM promoted the accumulation of Fe in GIST and decreased the GSH/GSSG ratio in a concentration-dependent manner. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | These results suggest that IM induces ferroptosis in GIST cells. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The mechanism of ferroptosis primarily involves classical pathways dependent on cysteine-glutamate antiporter (Systemxc-, is composed of SLC7A11 and SLC3A2) and GPX4 [34–36], and non-classical pathways such as abnormal lipid peroxide metabolism and iron metabolism . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | To clarify the specific molecular mechanism of IM-induced ferroptosis, we examined the effects of different IM concentrations and treatment durations on the expression of SLC7A11, GPX4, acyl-CoA synthetase long-chain family member 4 (ACSL4), ferritin-heavy polypeptide 1 (FTH1) and transferrin receptor 1 (TFR1) at the transcriptional level. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Our results indicated no significant effect on the expression of ACSL4 (Fig. S10). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The up-regulation of FTH1 and down-regulation of TFR1 may be caused by negative feedback (Fig. S10). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Therefore, we hypothesize that the mechanism of ferroptosis caused by IM may be through the classical ferroptosis pathway mediated by GSH, and this speculation was later confirmed by the significant decrease of GSH/GSSG ratio after IM treatment. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | SLC7A11 and GPX4 are the two most critical molecules in the classical ferroptosis pathway , in which no significant change was observed in the transcriptional and protein levels of SLC7A11, while GPX4 was significantly increased at the transcriptional level but significantly decreased at the protein level. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | These findings suggest that IM may regulate GPX4 expression through post-transcriptional modification. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | In addition, we found that IM increased the GPX4 mRNA levels, but this effect disappeared after adding proteasome inhibitor MG132, so we speculated that IM-induced GPX4 protein degradation may increase GPX4 mRNA levels through negative feedback (Figs. S11 and S12). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Interestingly, we found that RSL3 could lead to inhibition of GPX4 transcripts as well (Fig. S11). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | This observation suggests that RSL3 might influence GPX4 at multiple levels, potentially leading to a complex regulatory response. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | One possibility is that RSL3, by inhibiting GPX4 activity and leading to lipid peroxidation, triggers a cellular stress response that results in alterations in gene expression, including GPX4 mRNA. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | It is also possible that RSL3 has indirect effects on GPX4 regulation, possibly through signaling pathways or transcription factors that control GPX4 expression. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Further studies are needed to fully elucidate the mechanisms underlying the impact of RSL3 on GPX4 mRNA levels and to better understand the intricate regulatory networks involved in ferroptosis. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The glutathione peroxidase protein family (GPXs) is an important protein for cells to resist peroxidation. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | GPX4 is the sole lipid peroxidation-reducing GPXs, capable of converting lipid peroxidation bonds into hydroxyl groups, thereby nullifying peroxidation activity and preventing the buildup of lipid peroxides. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | GPX4 serves as a key negative regulator of ferroptosis, with the loss of GPX4 enzyme activity being the primary cause of ferroptosis. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Enhancing the inhibition of GPX4 expression or activity represents a novel strategy to augment ferroptosis effects. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | As a widespread post-translational modification, ubiquitin plays a vital role in biological regulation . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | We further detected the ubiquitination level of GPX4 after IM treatment and found that IM could promote the ubiquitination of GPX4. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Although the role of post-translational modification in ferroptosis has been gradually emphasized in recent years , it has been found that SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis in hepatocellular carcinoma , and ubiquitin-specific protease 7 (USP7) promotes ferroptosis via activation of the p53/TFR1 pathway , and NEDD4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | However, the research on GPX4 ubiquitin is very limited . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | To explore the specific molecules that mediate the ubiquitination of GPX4 induced by IM, we performed UbiBrowser website and found that STUB1 may be the E3 ubiquitin ligase of GPX4. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Our subsequent DRUGSURV database analysis also showed that STUB1 may be the indirect target of IM, and that IM could upregulate STUB1 expression, and knockdown of STUB1 effectively blocked the ferroptosis induced by IM. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | We subsequently investigated the specific mechanism by which STUB1 regulates GPX4. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | As a ubiquitin ligase, STUB1 functions by binding to substrates, promoting substrate degradation. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Currently, HMGB1 , ErbB2 and CIB1 have been identified as the substrates of STUB1. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Ubiquitin primarily regulates target proteins through covalent binding with substrate lysines. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | However, whether STUB1 regulates GPX4 through a similar lysine-related mechanism requires further investigation. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | In the present study, CO-IP results indicated that STUB1 inhibits GPX4 protein stability and promotes GPX4 ubiquitination through direct binding to GPX4. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | We constructed GPX4 deubiquitination point mutant plasmids (K107R, K126R, K162R, K167R, K191R). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Immunoprecipitation results revealed that ubiquitin levels of GPX4 significantly decreased following deubiquitination mutation at K191, with concurrent inhibition of GPX4 ubiquitination mediated by STUB1. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | This suggests that K191 is a key regulatory site for GPX4 ubiquitin modification catalyzed by STUB1. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Additionally, exploring more substrates could enhance our understanding of STUB1’s functions. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Apart from the GSH transport system, ferroptosis is regulated by ferroptosis suppressor protein 1 (FSP1). |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | FSP1 is a NAD(P)H-ubiquinone reductase, capable of reducing vitamin K to hydroquinone, a potent free radical trapping antioxidant, and an inhibitor of (phosphorus) lipid peroxidation. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | FSP1-dependent non-classical vitamin K cycling cooperates with GPX4 and glutathione to suppress lipid peroxidation and ferroptosis . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Whether STUB1 can regulate FSP1 requires further exploration. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | In summary, our data suggest that IM in GIST promotes the ubiquitination at site K191 of GPX4 by promoting the expression of STUB1, resulting in the degradation of GPX4 protein and induction of ferroptosis. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Previous studies have demonstrated that the efficacy of IM depends on the type of gene mutation, with patients harboring c-kit exon 11 mutations being more sensitive to IM than those with PDGFRA exon 18 D842V mutations . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Our study highlights that IM could induce ferroptosis in GIST through GPX4, yet GPX4 expression is heterogeneous in patients with GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | The expression of GPX4 was found to be negatively correlated with the prognosis of GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Generally, GIST patients with high expression of GPX4 may benefit more from IM treatment. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Further elucidating the potential mechanism of STUB1 and GPX4 in GIST and screening new drug combinations based on IM could represent a promising strategy for the treatment of GIST in the future. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | RSL3 is a specific inhibitor of GPX4 approved by the FDA, which has been shown to inhibit the growth, invasion, and metastasis of multiple cancers . |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Our data indicate that RSL3 and IM could synergistically inhibit the expression of GPX4 and promote ferroptosis both in vivo and in vitro. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Consequently, RSL3 demonstrates effective anti-tumor activity against GIST, and when combined with IM, it may offer additional treatment options for patients with GIST with poor responses to IM. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | However, it is important to acknowledge that our study has certain limitations. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Specifically, the use of immunodeficient BALB/c nude mice may restrict the generalizability of our findings to the broader context of ferroptosis’s impact on the immune system. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | This encompasses aspects such as the immune tolerance of late-stage ferroptotic cancer cells and the immunogenicity of early-stage ferroptotic cancer cells. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | As pictorially modeled in Fig. 8, this study for the first time demonstrates that IM induces ferroptosis in GIST by promoting STUB1-mediated GPX4 ubiquitination, offering a novel mechanism for the inhibition of GIST. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | Furthermore, combining IM with RSL3 presents a promising therapeutic strategy for GIST.Fig. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | 8Mechanism diagram of imatinib (IM) inducing ferroptosis. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | IM upregulates STUB1 expression. |
PMC10728200 | Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination | STUB1 overexpression promotes the ubiquitination of GPX4, thereby inducing ferroptosis in gastrointestinal stromal tumors (GIST). |
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