This study explores the combination of oncolytic adenoviruses with Erastin, a potent ferroptosis inducer, to enhance antitumor efficacy in oncolytic virus-insensitive cancer cell lines...This novel therapeutic approach has great potential to enhance the efficacy of oncolytic virotherapy in cancers resistant to oncolytic viruses by inducing ferroptosis. Further investigation in clinically relevant models is warranted to fully elucidate the underlying mechanisms and to optimize this combination strategy for potential clinical applications.
Furthermore, mitochondrial membrane potential was restored by increased voltage-dependent anion channel 1 (VDAC1) expression, and reactive oxygen species (ROS) levels in mitochondria and cytoplasm were reduced. These results suggest that He CAP exposure may be associated with modulation of mitochondrial ROS production and reduction of inflammation and ferroptosis, but whether mitochondrial repair contributes to these effects requires further investigation.
Furthermore, knockdown of MNX1-AS1 increased the sensitivity of NSCLC cells to the combination of RSL3 and paclitaxel. Taken together, our data suggest that MNX1-AS1 might be a potential therapeutic target for lung cancer, especially in combination of ferroptosis and/or apoptosis-inducing drugs.
7 days ago
Journal • PARP Biomarker • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • ABCG2 (ATP Binding Cassette Subfamily G Member 2) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4) • ANXA5 (Annexin A5)
In this study, we seek to determine whether 2-hydroxyestrone (2-OH-E1) and 2-hydroxyestradiol (2-OH-E2), 2 major metabolites of endogenous estrone (E1) and 17β-estradiol (E2) formed by cytochrome P450 in the liver, can protect against erastin- and RSL3-induced ferroptosis in hepatoma cells (H-4-II-E and HuH-7) in vitro and acetaminophen-induced mouse liver injury in vivo. This study shows that 2-hydroxyestrone and 2-hydroxyestradiol are 2 inhibitors of PDI that can strongly protect against chemically induced ferroptotic hepatocyte death in vitro and in vivo. This work supports a PDI-mediated, estrogen receptor-independent mechanism of hepatocyte protection by 2-hydroxyestrone and 2-hydroxyestradiol.
In conclusion, our findings demonstrate that DIC sensitized HCC cells to IKE-induced ferroptosis in HCC. Moreover, the identification of potential drugs that enhance the susceptibility of HCC cells to ferroptosis could provide novel therapeutic strategies for the treatment of HCC.
13 days ago
Journal • IO biomarker
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NQO1 (NAD(P)H dehydrogenase, quinone 1) • SLC7A11 (Solute Carrier Family 7 Member 11)
Ferroptosis was induced by either inhibiting glutathione peroxidase 4 (GPX4) using RSL3 or blocking all glutathione-dependent enzymes through inhibition of the glutamate/cysteine antiporter with Erastin. Our data suggest that ferroptosis induction in undifferentiated hBMSCs is primarily regulated by GPX4, whereas glutathione S-Transferase P1 (GSTP1) plays a key role in controlling ferroptosis in osteosarcoma cells. In conclusion, targeting the key pathways involved in ferroptosis across different bone cell types may improve the efficacy of cancer treatments while minimizing collateral damage and supporting regenerative processes, with minimal impact on cancer therapy.
13 days ago
Journal
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GSTP1 (Glutathione S-transferase pi 1) • GPX4 (Glutathione Peroxidase 4)
GPX4 suppression, alone or with current TNBC therapies, impacts outcomes in preclinical TNBC models with or without obesity and offers a new, plausible mechanistic target for TNBC treatment.
For in vivo application, RSL3@NP was co-delivered with CAP via injectable Pluronic hydrogel. In 4T1-bearing mice, hydrogel-mediated delivery of CAP and RSL3-loaded nanoparticles can effectively elicit potent anti-tumor immune responses and inhibit tumor growth.
Furthermore, silencing SLC7A11 or employing the ferroptosis inducer Erastin negated the promoting effect of METTL3 on NPC cell radioresistance. These findings suggest that METTL3 could be a novel therapeutic target for overcoming radiotherapy resistance in NPC.
14 days ago
Journal
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SLC7A11 (Solute Carrier Family 7 Member 11) • METTL3 (Methyltransferase Like 3)
We observed that EAAT3 knockdown, similar to NF-κB inhibition, led to the accumulation of reactive oxygen species (ROS) and increased sensitivity to ferroptosis induction by RAS-selective lethal 3 (RSL3)...These findings collectively emphasize the pivotal role of the NF-κB/EAAT3 axis in managing antioxidant stress and influencing lung cancer development. Moreover, this research offers insights into the potential for a combined ferroptosis therapy strategy in lung cancer treatment.
16 days ago
Journal
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NFKB1 (Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) • GPRC5A (G Protein-Coupled Receptor Class C Group 5 Member A)
Meanwhile, compared to the groups treated with either IFNβ or RSL3 alone, the combination treatment of IFNβ and RSL3 significantly inhibited the growth of HT1080 three-dimensional (3D) spheroids and tumor in a mouse xenograft model. Our work reveals a role for IFNβ in promoting ferroptosis and provides evidence that IFNβ could be used with RSL3 to increase cytotoxic effects in tumor cells.
Compared with the erastin and quercetin treated OPCs, increased rerrous iron, lipid peroxidation production, and decreased GSH content, as well as shrunken mitochondria, were observed in OPCs treated with a combination of erastin, quercetin, and rapamycin. In conclusion, our findings revealed that quercetin inhibits OPCs ferroptosis by blocking NCOA4-mediated ferritinophagy. Quercetin and ferritinophagy may be potential therapeutic agents for SCI.
Increased DUSP1 expression, correlated with higher Fe2+ and lipid ROS levels, was observed in gastric cancer cells with increasing Erastin concentration. The prognostic model effectively predicts gastric cancer patient outcomes. DUSP1 is lowly expressed in gastric cancer tissues and is associated with malignancy and metastasis, playing a role in ferroptosis in gastric cancer cells.
CA demonstrates a significant ameliorative effect on AMI in rats, with its underlying mechanism seemingly revolving around the regulation of ferroptosis via activation of the PI3K-AKT signaling pathway.
Additionally, knockout of NCOA4 significantly increased cell viability and GSH/GSSH ratio and reduced ROS levels in RSL3-treated cells overexpressing SIRT3...Autophagy inhibitor, SIRT3 or NCOA4 deletion significantly reduced the effects of puerarin on the autophagy-dependent ferroptosis in U87MG cells (all P < 0.05). SIRT3 drives sensitivity to ferroptosis by activating NCOA4-mediated autophagy, and we proposed puerarin, a promising therapeutic drug for glioblastoma.
In this study, the ferroptosis inducers (FINS) (erastin and RSL3) were found to increase ZFAS1 expression through the facilitation of SP1 binding to the ZFAS1 promoter. Altogether, this study demonstrates that ZFAS1 is a crucial element of ferroptosis in ccRCC, as it is responsible for the regulation of miR-185-5p and SLC25A28. Introducing ferroptosis could be a beneficial approach to treat ccRCC patients with high ZFAS1 levels.
The JMJD6 antagonist SKLB325 synergized with erastin in multiple pre-clinical PCa models. Together, this study identifies JMJD6 as a druggable vulnerability in SPOP-mutated PCa to increase sensitivity to ferroptosis inducers.
1 month ago
Journal
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AR (Androgen receptor) • SPOP (Speckle Type BTB/POZ Protein) • MBD4 (Methyl-CpG Binding Domain 4, DNA Glycosylase) • SLC7A11 (Solute Carrier Family 7 Member 11) • ATF4 (Activating Transcription Factor 4)
We have utilized human ovarian cancer cell lines, OVCAR-8 and its adriamycin-selected, multi-drug resistance protein (MDR1)-expressing NCI/ADR-RES, both equally sensitive to ER, to identify metabolic biomarkers of ferroptosis. Our studies identified several potential biomarkers of ER-induced ferroptosis including OPH, taurine, NAD+, NADP+ and glutamate in ovarian cancer cells. Identifying specific metabolic biomarkers that are predictive of whether a cancer is susceptible to ferroptosis will help us devise more successful treatment modalities.
ORes inhibits breast cancer cell growth by inducing ferroptosis through suppression of the EGFR/PI3K/AKT/GPX4 signalling axis. This study suggests that ORes holds promise as a potential therapeutic agent for breast cancer and warrants further investigation into its clinical applications and potential integration into existing treatment regimens.
Moreover, VSTM2L knockdown in PCa cells enhances the sensitivity of RSL3-induced ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and hexokinase 2 (HK2), enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for mitochondria-localized VSTM2L in driving ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.
Functionally, NF-κB p65 attenuated the PF-543-induced ferroptosis, and this effect was rescued by ferroptosis inducer erastin and RSL3. In vivo experiments also confirmed that the SPHK1 inhibitor increased olaparib sensitivity. A combination of SPHK1 inhibitors and olaparib may provide a therapeutic strategy for ovarian cancer.
Our observations indicate that the depletion of ILF3 impairs the malignant potential of BC cells and promotes their ferroptosis by downregulating CEP55 expression. Silencing ILF3 or CEP55 could represent a potential therapeutic strategy for BC treatment.
Erastin inhibited LLC cell proliferation and migration and promoted ferroptosis...Sh-YTHDF2 and DNase I inhibited NETs formation in tumours, increased the activity of CD8(+) T cells and inhibited LUAD growth. Our results suggested that NETs promoted the growth of LUAD through inhibiting ferroptosis and CD8(+) T cell activity by promoting YTHDF2-mediated SLC2A3 mRNA degradation.
The oxidization of the cell membrane lipids may suppress EMT, including cell migration. Since EMT is a major malignant phenotype of PDAC, our findings may lead to the advancement of PDAC therapy, especially in the prevention of postoperative recurrence.
Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma.
Morphology studies and cell death analyses confirmed that a combination treatment of ferroptotic agent erastin (ERA) and apoptotic agent TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) synergistically enhances TRAIL-induced apoptosis in human pancreatic adenocarcinoma BxPC3 and human colorectal carcinoma HCT116 cells...Moreover, ERA enhanced Mcl-1 inhibitor-induced apoptosis. Collectively, our studies suggest that Mcl-1 is a gatekeeper molecule between the ER stress pathway and the mitochondria-dependent apoptotic pathway.
However, whether blocking the intrinsic ferroptosis pathways of MDSCs can relieve imidazole ketone erastin (IKE)-initiated ferroptosis-induced immune suppression and ultimately trigger the optimal therapeutic effect of the combined ferroptosis and ICB therapy is still unknown...More importantly, TIPE2-deficient MDSCs achieved the full anti-tumor therapeutic potential of IKE-induced ferroptosis therapy and a PD-L1 blockade. These findings indicate that TIPE2 confers the ferroptosis sensitivity of MDSCs, and combining the targeting of the TIPE2 of MDSCs, ferroptosis therapy, and ICB is a novel therapeutic option for cancer treatment.
2 months ago
Journal
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GPX4 (Glutathione Peroxidase 4) • SLC7A11 (Solute Carrier Family 7 Member 11)
Combining ROR1 CAR-T cells with ferroptosis inducers enhanced anti-tumor efficacy in NSCLC by promoting ferroptosis through increased lipid peroxidation.
2 months ago
Journal • IO biomarker
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IFNG (Interferon, gamma) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4)
METTL7B is involved in BC development and progression. METTL7B may mediate m6A modification on ACSL3 mRNA to negatively regulate ferroptosis in BC cells, which provides a potential therapeutic target for BC via ferroptosis.
Importantly, the system xc- inhibitor Sorafenib or Imidazole ketone erastin effectively inhibited the growth of tamoxifen-resistant breast cells in vitro and in vivo. In conclusion, our data reveal that targeting estrogen-regulated SLC7A11 and SLC3A2 enhances ferroptosis in ER+ breast cancer, offering a novel therapeutic option for patients with ER+ breast cancer, particularly those with endocrine resistance.
2 months ago
Journal
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SLC3A2 (Solute Carrier Family 3 Member 2) • SLC7A11 (Solute Carrier Family 7 Member 11)
These findings position CT-1 as a promising therapeutic agent, offering a strategy to combat TNBC by inducing ferroptosis in both N2-type TANs and cancer cells. This approach underscores the potential of FTH1 as a therapeutic target for treating TNBC.
APS was shown to reduce the protein and mRNA expression of Nrf2, SLC7A11, and GPX4(P<0.01), with the APS+RSL3 showing even more significant effects(P<0.001). In conclusion, APS can induce ferroptosis in ovarian cancer cells, and its mechanism may be related to the regulation of the Nrf2/SLC7A11/GPX4 signaling pathway, providing an experimental basis for the use of APS injections in the treatment of ovarian cancer.
2 months ago
Journal
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GPX4 (Glutathione Peroxidase 4) • SLC7A11 (Solute Carrier Family 7 Member 11)
METTL3 regulated the transcription of SLC7A11 through GATA3 and KDM6B to modulate ferroptosis in an m6A-dependent manner. This study provides a novel potential strategy and experimental support for the future treatment of cancer.
2 months ago
Journal
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KDM6B (Lysine Demethylase 6B) • SLC7A11 (Solute Carrier Family 7 Member 11) • GATA3 (GATA binding protein 3) • METTL3 (Methyltransferase Like 3) • YTHDF2 (YTH N6-Methyladenosine RNA Binding Protein 2) • YY1 (YY1 Transcription Factor)
Ferroptosis can serve as a potential therapeutic target for CRPC, and could be a new strategy for combination therapy. Moreover, ferroptosis-related genes may be great indicators of PCa prognosis. Further research on ferroptosis in CRPC therapy can benefit from the frameworks provided by this review.
Overexpression of SOX13 enhances the inhibition of RSL3 (iron death activator) on the cell viability of TPC-1...In addition, SOX13 strongly regulates cancer immunity and Ferroptosis. Hence, SOX13 has great promise as a bioindicator for both thyroid cancer prognosis and immune cell invasion.
Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.
The depletion of PRKAA2 enhanced the erastin-induced inhibition effect on cell growth, and notably increased the levels of MDA, ROS, iron, and Fe2+, while decreased GSH level in NSCLC cells...The results discovered that PRKAA2 accelerated the malignant progression, diminished apoptosis and ferroptosis in NSCLC through SLC7A11/GSH/GPX4 pathway. This study provide a novel target in the application of PRKAA2 for NSCLC treatment.
Here, pH-responsive DSPE-PEoz modified hollow Bi2Se3-RSL3/diABZi (DP-HBN/RA) nanomedicine is designed as a radiation sensitizer for efficient treatment of triple-negative breast cancer by simultaneously amplifying ferroptosis and immune system activation...Ingeniously, the released diABZi reinforces cGAS-STING activation to boost the immunology antitumor effect. This work links the induction of ferroptosis and the initiation of systematic immune response to achieve highly effective tumor suppression, which opens up new avenues for future treatments of refractory tumors.
In this study, a neurotransmitter-mimicking nanovesicle (PMVS-P) based on platelet membrane-derived vesicle (PMV) with anti-GSC drug salinomycin (SAL)-loading and polydopamine (PDA)-surface is synthesized. PMVS-P exhibits surgical incision targeting ability and specifically identified GSCs with highly expressed D2 dopamine receptor (D2DR), a central nervous system neurotransmitter receptor, thus suppressing GBM recurrence. This neurotransmitter-mimicking nanovesicle primed GSC-specific tumoricidal treatment with broadened applications for preventing tumor recurrence.
Using a panel of CCA cell lines, we confirmed ACSL3 upregulation in CCA cell lines associated with high-risk CCA, correlating this with resistance to the ferroptosis inducer RSL3...Resistance to ferroptosis was also dependent on exogenous MUFAs and was enhanced by lipid droplet biogenesis inhibition. These findings highlight ACSL3 as a promising target for therapeutic strategies aimed at overcoming ferroptosis resistance in CCA.
3 months ago
Journal
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ACSL3 (Acyl-CoA Synthetase Long Chain Family Member 3)