RSL3

Then, we performed RNA sequencing to compare gene expression between parental and RR cells, and cells pretreated with or without RSL3...Overall, our findings identify ferroptosis inactivation linked with resistance to radiotherapy. Besides, NUPR1 can promote radiation resistance by inhibiting ferroptosis, and targeting NUPR1 may be a potential strategy to relieve radioresistance associated with ferroptosis in CRC.

In vivo experiments showed that RSL3 significantly suppressed primary myeloma growth, which could be rescued by the micropeptide altKLF4. Taken together, our study identifies altKLF4 as a novel micropeptide that serves as a potential biomarker for chemotherapeutic resistance in multiple myeloma, offering insights for diagnosis and management of drug-resistant MM.

Blockade of the WTX-L/β-arrestin2/NF-κB/LCN2 axis significantly diminished the activity of ferroptosis inducers (erastin and RSL3) in vivo. Collectively, these findings reveal that targeting the ferroptosis vulnerabilities through WTX-L may represent a promising strategy for GC.

Both OA and POA could protect cancer cells from the killing effects of the ferroptosis inducer erastin and RSL3, and OA had a stronger protective effect than POA, resulting in lower lipid ROS production than POA. A mouse model demonstrated that ACSL3 knockdown combined with imidazole ketone erastin synergistically enhanced antitumor effects in radiation-resistant tumors in vivo. Our study reveals previously undiscovered associations between radiation and fatty acid metabolism and ferroptosis, providing a novel treatment strategy for overcoming cancer radioresistance.

LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces cancer cell viability, which is potentiated by the ferroptosis inducer RSL3...Finally, radiation therapy induces mitochondrial lipid peroxidation and reduces tumor growth, which is further enhanced when combined with LDHB silencing. Thus, LDHB-mediated lactate oxidation drives the CoQ-dependent suppression of mitochondria-associated ferroptosis, a promising target for combination therapies.

Collectively, the findings indicate that PV could alleviate MI/R injury by inhibiting oxidative stress and ferroptosis via the NRF2/GPX4 pathway, and ursolic acid is the main active component responsible for mediating both antioxidative and anti-ferroptosis effects, suggesting its potential use as a therapeutic agent against MI/R injury.

These findings suggest that medium-chain fatty acids could be developed as novel ferroptosis sensitizers to enhance ferroptosis-based cancer therapy.

The relationships between NCOA6 and ACSL4 or SCD1 are further explored in clinical specimens. This study reveals that targeting NCOA6 might alleviate gemcitabine resistance in pancreatic cancer.

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.

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.

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.

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.

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.

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.

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.

Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.

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.

These findings were also confirmed in a BCRP-expressing human breast cancer cell line (MCF-7/MXR), which was selected for resistance to Mitoxantrone. RSL3 also significantly increased Topotecan cytotoxicity. Our findings-demonstrating increased cytotoxicity of Adriamycin and Topotecan in P-gp- and BCRP-expressing cells-suggest that ferroptosis inducers may be highly valuable in combination with other chemotherapeutics to manage patients' cancer burden in the clinical setting.

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.

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.

The COX-2 inhibitor celecoxib effectively sensitized nasopharyngeal cancer cells to ferroptosis induction.

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.

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.

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.

Knockdowning and blocking JAM3 sensitized cancer cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance to these agents. In addition, JAM3 also promoted ovarian cancer cells resistance to chemotherapeutic agent cisplatin in vitro and in vivo by inhibiting ferroptosis...Moreover, JAM3 high expression was associated with poor prognosis in patients with ovarian cancer. Altogether, this study provided novel insights into the molecular mechanisms underlying ferroptosis resistance and identify JAM3 as a potential therapeutic target for combating drug resistance in ovarian cancer.

Mitophagy-deficient tumors lack this anti-ferroptotic mechanism, unleashing the generation of lipid peroxidation and potent ferroptotic cell death induced by erastin, RSL3, cysteine deprivation, radiotherapy, and immunotherapy. In summary, patient-derived organoids of colorectal cancer patients for screening ferroptosis-sensitive tumors are established, providing a paradigm for identifying that patient-derived tumors are sensitive to ferroptosis-inducing therapies. This study concludes that mitophagy-deficient tumors are vulnerable to ferroptosis induction, which may lead to the development of new therapeutic strategies for tumors deficient in mitophagy.

Using the NOD-scid IL2Rgammanull (NSG) mouse based xenograft model and intra-bone MM growth model, we validated that target SENP3 enhanced the killing effect of GPX4 inhibitor RSL3, thereby reduced tumor burden, prolonged survival of mice, and alleviated bone disruption of mice bearing MM tumors. Our study deciphers the mechanism of BMSCs preventing MM cells from spontaneous ferroptosis, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients.

Herein, a versatile nanoplatform, CeO2@CuO2@DOX-RSL3@HA (CCDRH), was initially constructed for promoting the antitumor efficiency via regulation of the TME...The experimental results revealed that CCDRH exhibited high performance in tumor inhibition, which is attributed to the combined effect of enhanced chemotherapy, ferroptosis and cuproptosis. The study provides a new approach for improving anticancer efficiency via regulation of the TME.

We found that lithium significantly enhanced RSL3-induced ferroptosis in vitro, evidenced by increased mitochondrial peroxide, lipid peroxidation, and mitochondrial abnormalities...Additionally, this combination enhanced CD8+ T cell infiltration and IFN-γ expression in the tumor microenvironment, especially among cytotoxic effector CD8+ T cells. These findings reveal the pro-ferroptotic and immune regulation roles of lithium, broaden our understanding of its biological roles, and propose new strategies for ferroptosis-targeted therapies in melanoma.

Cells cultured in FBS containing higher selenium concentrations exhibited elevated GPx4 expression, and were resistant to ferroptosis induced by erastin and RSL3. These findings suggest that the variability of selenium content in different FBS batches can significantly influence the susceptibility of cells to ferroptosis, highlighting the importance of standardizing these factors to enhance the reproducibility of ferroptosis-related experiments.

The computed binding free energies for RSL3, isochondrodendrine, hinokiflavone, irinotecan and ginkgetin were -80.12, -107.31, -132.03, and -137.52 and -91.11 kJ/mol, respectively, indicating their significantly higher inhibitory effects compared to RSL3. These findings highlight the potential for developing novel GPX4 inhibitors to promote ferroptosis, warranting further experimental validation.

In this study, we proved that iberverin can induce intracellular reactive oxygen species (ROS) generation to inhibit cell proliferation and initiate ferroptotic cell death in HCC cells, which can be eradicated by the ferroptosis inhibitor ferrostatin-1 (Fer-1) or deferoxamine mesylate (DFO) and ROS scavenger (GSH or NAC). Significantly, a low dose of iberverin can remarkably increase the sensitivity of HCC cells to ferroptosis induced by canonical ferroptosis inducers RSL3 and imidazole ketone erastin (IKE). This study uncovers a critical function of iberverin in preventing HCC through ferroptosis and provides a promising strategy for HCC treatment either via iberverin alone or in combination with canonical ferroptosis inducers in the future.

Taken together, our findings suggest that propafenone holds promise as a candidate drug for enhancing the efficacy of immunotherapy and other ferroptosis-targeted therapies in the treatment of melanoma.

Furthermore, in mice bearing human U87 tumor xenografts, RSL3 administration synergized with IR to inhibit tumor growth, accompanied by TGM2 inhibition, DNA DSBs, and EMT inhibition in tumor tissues. Taken together, we demonstrated that RSL3 sensitizes glioma cells to IR by suppressing TGM2-mediated DNA repair and EMT.

BC13 demonstrates profound synergistic antitumor effects with ferroptosis inducer in TNBC cells. Therefore, BC13 is a novel dual inhibitor of CDK6/BRD4 for the treatment of TNBC either as a single agent or in combination with RSL3.

Moreover, REEP6 overexpression conferred resistance to RSL3, a ferroptosis inducer, whereas REEP6 knockdown sensitized OSCC cells to RSL3...In addition, we identified promoter DNA hypomethylation as the underlying cause of REEP6 overexpression in OSCC. Taken together, REEP6 acts as a novel suppressor of ferroptosis, with its overexpression driven by promoter hypomethylation contributing to OSCC progression by ER stress-mediated ferroptosis via ACSL4.

Mechanistically, TMOD3 promoted F-actin polymerization, thereby facilitating the fusion of autophagosomes with lysosomes, increasing the degradation of the ACSL4 protein, and augmenting the ferroptosis-inducing effects of RSL3...Cangrelor, an FDA-approved drug, can target TMOD3...In conclusion, TMOD3 was found to inhibit ferroptosis and induced the resistance to PD-1 antibody by facilitating the fusion of autophagosomes and lysosomes through the promotion of F-actin polymerization in KRAS-mutant PC. TMOD3 was identified as a novel target for PC therapy.

The autophagy inhibitor bafilomycin or chloroquine alleviated autophagy-dependent degradation of ferritin protein under RSL3 treated condition. Additionally, a colocalization of CYGB with the transferrin receptor (TFR) was confirmed. Our results demonstrate an important functional pathway by which CYGB regulates ferroptosis through TFR-binding and autophagic degradation of ferritin, and provide a potential pathway for the treatment of colorectal cancer.