RSL3 / Stanford University - LARVOL DELTA

Inhibition of FSP1 enhances venetoclax induced cell death in Acute Myeloid Leukemia by the ferroptosis pathway (ASH 2025) - "Methods AML cell lines THP-1 and Kasumi-1 were treated with idarubicin (IDA), venetoclax, the ferroptosis inducer RSL3, the inhibitor Ferrostatin-1, and the ferroptosis suppressor protein 1 (FSP1) inhibitor iFSP1. FSP1 inhibition increased the sensitivity of AML cells to venetoclax via the ferroptosis pathway. iFSP1 in combination with venetoclax may provide a favorable strategy for AML treatment."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • AIFM2 • ATG7 • BCL2 • GPX4 • MYCN • PACERR • PTGS2 • SLC7A11 • TLR4

Polyunsaturated fatty acids control lipid membrane dynamics and ferroptosis sensitivity in B-cell lymphoma (ASH 2025) - "We uncovered that B-cell lymphomas are highly enriched in PUFA and selectively dependent on pro-ferroptotic PUFAmetabolism to maintain competitive fitness and lipid membrane properties, which endows them with anintrinsic vulnerability to ferroptotic cell death. Our comparative analyses of public drug screening data (CTD, GDSC) and a validation screen weperformed uncovered that B-cell lymphomas are the most sensitive type of tumor to all evaluatedferroptosis inducers, including GPX4 inhibitors (RSL3, ML210), the inhibitor of the cystine/glutamateantiporter system Xc- erastin, and the iron oxidizer FINO2. We show that B-cell lymphomas are selectively dependent on PUFA metabolism to maintainmembrane properties and competitive fitness. However, this intrinsic metabolic dependency is a keyfactor making them highly vulnerable to ferroptosis. Our findings also provide insight into B-celllymphoma metabolism and lipid membrane dynamics, and how it could be leveraged as a..."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • ACSL3 • ACSL4 • GPX4

A genome-wide CRISPR screen identifies conventional and novel ferroptosis regulators in Acute Myeloid Leukemia (ASH 2025) - "Our data has shown that the inhibition of GPX4 with a specificinhibitor, ML210, induces mitochondria-dependent ferroptosis even in venetoclax-resistant AML cells.However, the prolonged survival of AML xenograft mice by GPX4 knockdown in vivo is limited...Genomic DNA was prepared fromthe cells collected after 9 days of doxycycline treatment and used as the template for amplifying thesgRNA library with a modified two-round of PCR...Based on re-analyses of publicly available databases, theexpression of MAFG is positively correlated with GPX4 expression in AML and with the resistance toseveral ferroptosis inducers, including ML162, ML210, and RSL3...We performed a genome-wide CRISPR knockout screen using a GPX4 genetic knockdown model andidentified multiple known and novel ferroptosis regulators in AML cells. Specifically, our data suggestsMAFG as a novel potential ferroptosis suppressor in AML. Further mechanistic studies are ongoing."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Osteosarcoma • Sarcoma • Solid Tumor • Targeted Protein Degradation • ACSL4 • AIFM2 • DHCR7 • GPX4 • SLC7A11

RXR agonist IRX4204 induces ferroptosis in multiple myeloma via HMOX1/GPX4 axis and enhances lenalidomide efficacy (ASH 2025) - "To ultimately combine IRX4204 with lenalidomide for clinicalapplication, our current study investigated the effects and underlying mechanism of IRX4204 inenhancing lenalidomide anti-myeloma activity.Human MM cell lines (MM1.R and U266) were treated with IRX4204 (1µM), the ferroptosis inducer/GPX4inhibitor RSL3 (2 µM), lenalidomide, or combinations. IRX4204 promotes ferroptosis in MM cells by activating the PPARα/RXRα-HMOX1 axis and suppressingGPX4/SLC7A11-mediated antioxidant defense. This effect enhances the therapeutic efficacy oflenalidomide, both in vitro and in vivo. The correlation between high HMOX1 expression and improvedpatient survival suggests clinical relevance of this pathway."

Clinical • Hematological Malignancies • Multiple Myeloma • GPX4 • HMOX1 • PPARA • SLC7A11

RXR agonist IRX4204 enhances BCMA CAR-T-cell efficacy by suppressing ferroptosis via CHAC1 downregulation (ASH 2025) - "Ferroptosis involvement was further examined bychallenging CAR-T cells with RSL3 (Ferroptosis inducer) and Ferr-1 (Ferroptosis inhibitor) in the presenceor absence of IRX4204. The clinical correlation between high RXR expression and superior CAR-T outcomesunderscores the relevance of this pathway. Our findings lay the groundwork establishing RXR agonism asa promising strategy to improve CAR-T cell persistence and the durability of responses in MM. Thesepreclinical results provide a strong rationale for clinical translation, warranting exploration of thecombination strategy of IRX4204 plus CAR-T in future clinical trials."

CAR T-Cell Therapy • Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • CD4 • CD69 • CHAC1 • GPX4 • PPARA • SLC7A11

ENO1 promotes Acute Myeloid Leukemia progression through SCD1-mediated lipid metabolism reprogramming (ASH 2025) - "Notably, weobserved that ENO1KD AML cells exhibited an increased feroptosis, and displayed heightened sensitivityto ferroptosis inducer RSL3, suggesting a role for ferroptosis regulation in ENO1-mediated tumorprogression.To delineate and characterize the molecular pathways governing ENO1-mediated AML progression andferroptosis resistance, we performed RNA sequencing (RNA-seq) on ENO1KD MV4-11 cells. Moreover, the elevated monounsaturatedfatty acids catalyzed by SCD1 are subsequently incorporated into the membrane phospholipids of AMLcells, leading to increased resistance to lipid peroxidation and ferroptotis.Based on these results, we found that combining an SCD1 inhibitor with daunorubicin (DNR), which caninduce ferroptosis in tumor cells, effectively reduced the resistance to ferroptosis in AML cells exhibitinghigh ENO1 expression. Overall, our study elucidates the mechanism by which ENO1 directly 8regulatesSCD1, driving lipid reprogramming and alterations in membrane..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • ENO1 • SCD

Ferroptosis activates NK and CAR T cell-mediated anti-tumor immunity in Acute Myeloid Leukemia (ASH 2025) - "Resistance to apoptosis remains a major clinical challenge in acute myeloid leukemia (AML), especially inrelapsed/refractory (R/R) cases following standard therapies including venetoclax (VEN) -containingregimens...As the immunogenicity of ferroptosis is highlycontext-dependent, it is critical to elucidate the immunogenic properties of ferroptosis specifically in AMLto develop tailored immune-potentiating therapeutics.To investigate whether GPX4 inhibition induces ICD signaling in AML, we applied a doxycycline (dox)-inducible GPX4-knockdown (KD) system in MOLM-13 cells and assessed key DAMPs including ATP,HMGB1, and calreticulin (CRT), using CTG assay, ELISA, and flow cytometry, respectively...Pharmacological inhibition of GPX4 by RSL3 also demonstrated a time-dependent increase in ATP,HMGB1, and CRT levels in MOLM13 cells, all of which were also suppressed by Fer-1...Consistent results were observed upon treatment with theselective GPX4 inhibitor ML210 in both MOLM13..."

CAR T-Cell Therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CALR • CD123 • GPX4 • HMGB1 • IL3RA

Ferroptosis escape in AML stem cells uncovered by single-cell profiling and reversed by STAT3/NRF2 inhibition (ASH 2025) - "These cells were treated with STAT3 inhibitor C188-9 or STAT3-NRF2dual inhibitor (Brusatol) and the effect on cell proliferation was determined using CCK-8 assay, geneexpression by qPCR, flow cytometry was used for the detection of lipid ROS levels by Bodipy dye andintracellular iron estimation were performed...Moreover, acombination of NRF2-STAT3 inhibitor potentiated the effect of ferroptosis inducers RSL3 and Erastin andenhanced the cytotoxicity in LSCs.Our scRNAseq analysis of enriched AML LSCs revealed and dissected the mechanistic differencesbetween LSCs and non-LSCs...Our findings suggest that promoting ferroptosis is indeed apromising strategy to combat chemoresistance in AML. Therefore, dual targeting of NRF2-STAT3 alongwith ferroptosis inducers hold potential as adjuvant therapy by promoting ferroptosis-mediated celldeath in AML LSCs."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD34 • FTH1 • GPX4 • KIT • STAT3

Vitamin K3 metabolic fate determines pro-survival or ferroptotic outcomes in multiple myeloma via UBIAD1 and reductase axis (ASH 2025) - "Ferroptosis InhibitorSpecificity: Cell death induction by vitamin K3 (78%) was significantly attenuated by the ferroptosisinhibitor Liproxstatin-1 (reduced to 32%; P<0.01), whereas apoptosis inhibitors failed to confer protection.We establish that the functional duality of vitamin K3 is governed by its metabolic processing throughUbiA prenyltransferase domain-containing protein 1 (UBIAD1) and reductase enzymes. Specifically, inMM1S myeloma cells, low-dose vitamin K3 (1 μM) is metabolized to vitamin K2 by UBIAD1, therebyaugmenting cellular antioxidant capacity and rescuing cells from RSL3-induced ferroptosis...Mechanistically, single-electron reduction generatesunstable semiquinone radicals, propagating lipid peroxidation—a hallmark of ferroptosis.Clinical validation utilizing patient-derived organoids (PDOs) established from primary myeloma cells of 8patients revealed that sensitivity to vitamin K3 correlated with low UBIAD1 expression and elevated levelsof..."

Hematological Malignancies • Multiple Myeloma • AIFM2 • GPX4 • NQO1

Selenocysteine dependency renders central nervous system leukaemia therapeutically sensitive to ferroptosis (ASH 2025) - "Exposure of both B- and T-ALLcells to this media resulted in significantly increased lipid peroxidation, triggered the GSH stress markerCHAC1, and increased sensitivity to the ferroptosis-inducing compounds RSL3 (inhibitor of GPX4) andErastin (inhibitor of cystine antiporter System XC-)...GSH disruption (by cystine deprivation in CSF media, or Erastin) inLRP8KO and SEPHS2KO cells resulted in increased lipid peroxidation, selective loss of GPX4 expression andenhanced ferroptosis... By comprehensive in vitro and in vivo characterisation we have identified a pivotalmechanism underpinning leukaemic survival in the CNS-niche. We show that the unique biochemicalcomposition of CSF drives a dependence on selenocysteine biosynthesis which presents a targetablemetabolic vulnerability. Our demonstration that Auranofin, a repurposed FDA-approved oral compoundwith excellent tolerability, leads to selective eradication of CNS-leukaemia in PDX models paves the wayfor clinical advances..."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • GPX4 • SELENOP • SEPHS2

AGR2 blocks ferroptosis through the p53/FPN1 circuit and unmasks treatment targets in pancreatic cancer (ESMO Asia 2025) - "To assess the functional consequences of AGR2-mediated p53 suppression, we conducted ferroptosis assays using RSL3 as an inducer... Our study shows that blocking AGR2-dependent FPN1 expression undermines ferroptosis resistance in pancreatic ductal adenocarcinoma (PDAC) cells both in vitro and in vivo. AGR2 levels positively correlate with FPN1 in pancreatic tumor tissues, and this association is linked to poorer patient outcomes. Consequently, targeting the AGR2/p53/FPN1 axis may suppress tumor growth and enhance ferroptosis-based therapies."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AGR2

Hydrogen alleviates cardiac ferroptosis damage under chronic intermittent hypoxia conditions by targeting Nrf2. (PubMed, Int Immunopharmacol) - "These findings suggested that hydrogen could promote autophagy and reduce oxidative stress by activating the Nrf2 protein, thereby inhibiting ferroptosis and alleviating cardiac damage caused by CIH."

Journal • Cardiovascular • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Gentianine suppresses renal cell carcinoma progression via direct interaction with KDM5B and ferroptosis activation. (PubMed, Cell Signal) - "Importantly, combining GTN with the ferroptosis inducer RSL3 synergistically enhances antitumor efficacy in vivo. Our study unveils a previously unrecognized KDM5B/ferroptosis axis through which GTN exerts its antitumor effects, positioning GTN as a promising lead compound for ferroptosis-targeted therapy in RCC."

Journal • Genito-urinary Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • GPX4 • KDM5B • SLC7A11

Licochalcone A promotes SP1/DNA-PKcs-dependent NHEJ repair to prevent ferroptosis and attenuate hepatic ischemia-reperfusion injury. (PubMed, Phytomedicine) - "Our findings establish a novel connection between DNA repair pathways and ferroptosis suppression, positioning LA as a unique therapeutic candidate. By targeting the SP1/DNA-PKcs axis, this study not only provides a mechanistic foundation for LA-based therapies but also highlights its translational potential for treating ferroptosis-related diseases."

Journal • Cardiovascular • Reperfusion Injury • PRKDC • SP1

Sanqi Qushi formula alleviates podocyte damage in passive Heymann Nephritis rats by inhibiting GPX4 deficiency-mediated ferroptosis via the JNK/FoxO1 signaling pathway. (PubMed, Phytomedicine) - "These results suggest that SQQS may alleviate podocyte damage by inhibiting GPX4 deficiency-mediated ferroptosis through targeting JNK1 to decrease the nuclear translocation of FoxO1."

Journal • Preclinical • Glomerulonephritis • Nephrology • Renal Disease • ACSL4 • GPX4 • MAPK8

Synthesis and evaluation of lupeol-derived triterpenic azines as potential neuroprotective agents. (PubMed, RSC Med Chem) - "Since ferroptosis is a cell death mechanism implicated in PD, we further examined the effects of these compounds in N27 dopaminergic neurons exposed to the ferroptosis inducers RSL3 and erastin. Among the tested derivatives, 4c exhibited a remarkable protective effect against RSL3-induced ferroptosis, which was comparable to ferrostatin-1, displaying an IC50 value of 9.1 μM. These findings support the development of triterpenic azines as neuroprotective agents and warrant further investigation in preclinical PD models."

Journal • CNS Disorders • Movement Disorders • Neuroblastoma • Oncology • Parkinson's Disease • Solid Tumor

ZK53 enhances tumor cell susceptibility to ferroptosis via ClpP-mediated mitochondrial dysfunction. (PubMed, Front Oncol) - "In this study, through functional screening, we identified ZK53, a small molecule that sensitizes cells to the ferroptosis inducer RSL3...In vivo, ZK53 synergized with ferroptosis inducers IKE to significantly inhibit tumor growth in xenograft models by promoting ferroptosis. Taken together, our findings identify ClpP as a novel target for ferroptosis and suggest that ZK53 may serve as a promising candidate for enhancing ferroptosis-based cancer therapy."

Journal • Metabolic Disorders • Oncology

The microbial metabolite I3A inhibits ferroptosis and the effectiveness of redox-based cancer therapy. (PubMed, J Biol Chem) - "In mouse models of melanoma and colorectal cancer, I3A administration significantly reduced the antitumor efficacy of the ferroptosis inducer RSL3, accompanied by reduced lipid peroxidation and preserved GPX4 levels. Furthermore, gut colonization with Lactobacillus reuteri increased I3A concentration and conferred ferroptosis resistance in vivo. Together, these findings identify a host-microbe metabolic axis in which microbial I3A suppresses cancer cell ferroptosis through AHR-JNK signaling, which may have critical implications for redox-based cancer therapies."

Journal • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • GPX4

Phloretin inhibits ferroptosis by restoring the antioxidant capacity of bovine adipose and muscle cells via the AMPK-PPAR signaling pathway. (PubMed, Stress Biol) - "Herein, phloretin was verified to significantly inhibit (1S,3R)-RSL3-induced ferroptosis by reducing intracellular MDA, Fe2⁺, and ROS levels and restoring cell total antioxidant capacity in bovine and mouse preadipocytes or myoblasts...Further transcriptomic analyses of mouse adipose tissues revealed that phloretin alleviated ferroptosis in adipocytes by modulating the transcription of genes enriched in AMPK and PPAR signaling pathways, such as Camkk2. Hence, based on multi-omics analysis combined with in vivo and in vitro verification, phloretin effectively alleviated the OS to further inhibit ferroptosis of adipose or muscle cells through the AMPK-PPAR pathway, which can provide new research ideas for ameliorating adipose or myocyte dysfunction induced by ferroptosis in animals."

Journal • Metabolic Disorders • Obesity • ACSL4 • GPX4 • PACERR • PTGS2

EMP1-driven Ferroptosis in Liver Sinusoidal Endothelial Cells Exacerbates Hepatic Ischemia-Reperfusion Injury via P38 MAPK. (PubMed, Free Radic Biol Med) - "In LSECs and BRL3A hepatocytes subjected to hypoxia/reoxygenation (H/R), EMP1 silencing with an siRNA, ferroptosis modulation via ferrostatin-1 (Fer-1) or RSL3, and p38 signaling intervention using the p38 activator berberine chloride collectively revealed that EMP1 drives ferroptosis in LSECs in a p38-dependent manner...Furthermore, EMP1 exerted its effects solely via p38 signaling and its depletion selectively abolished p38 phosphorylation, whereas the p38 activator berberine chloride fully reinstated ferroptotic phenotypes and hepatocyte injury. Collectively, these data establish EMP1/p38-driven LSEC ferroptosis as a direct cause of hepatocyte damage, offering a fundamentally new perspective on the pathogenesis of hepatic ischemia reperfusion injury (HIRI) and a novel, potentially targeted therapeutic strategy for its prevention and treatment."

Journal • Cardiovascular • Hepatology • Liver Failure • Otorhinolaryngology • Reperfusion Injury • Transplantation • ACSL4 • GPX4 • VCAM1

Ferroptosis-induced remodeling of glycosylation the immune microenvironment and improves survival in pancreatic cancer. (PubMed, World J Surg Oncol) - "Firstly, the dual pathway specific enrichment strategy of O-GlcNAc modified peptides and N-glycosylated peptides was applied to ferroptosis study for the first time, which realized a systematic analysis of glycosylation patterns in the process of cell death. Secondly, high-resolution mass spectrometry combined with multi-platform data processing (MaxQuant/PEAKS) was used to deeply integrate transcriptomes and single-cell transcriptomes to construct a panoramic analysis framework with multi-omics mutual evidence. Thirdly, Scissor method was introduced to map TCGA ferroptosis pathway activity to single-cell data to achieve cross-scale analysis from population level to cell subsets. Fourth, combined with multi-dimensional bioinformatics tools, the characteristics of modification sites, subcellular localization, protein interaction network and functional pathway were annotated. Fifth, on the basis of multi-omics results, double-layer validation by qPCR and Western Blot at..."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • FADS2 • IL17A • SNCA

Utilization of DOX-Fe complex and RSL3 co-loaded liposomes in ferroptosis-enhanced treatment of triple-negative breast cancer. (PubMed, Drug Deliv) - "Here, we reported a doxorubicin (DOX)-Fe complex and RSL3 co-loaded liposomes (DOX-Fe/RSL3@LIPs) for ferroptosis-enhanced chemotherapy on TNBC tumors. The tumor cell ferroptosis was observably enhanced via supplements of the ferrous ions and H2O2, and RSL3-derived GPX4 inhibition to severely destroy the oxidation balance in cells. In this paper, the DOX-Fe/RSL3@LIPs have exerted a synergistic anticancer effect on TNBC by combining ferroptosis and conventional chemotherapy, and made a meaningful exploration of new strategies for TNBC therapy."

Journal • Breast Cancer • Cardiovascular • Oncology • Solid Tumor • Triple Negative Breast Cancer • GPX4

NOTCH3 mediates metabolic reprogramming and ferroptosis resistance in meningiomas (SNO 2025) - "Finally, CH157-MNNOTCH3 ICD cells exhibited increased resistance to RSL3-induced ferroptosis, a phenotype reversed with CPT1 inhibition. These data establish a link between NOTCH3 signaling, lipid metabolic reprogramming, and ferroptosis evasion in aggressive meningioma cells. This metabolic shift may contribute to the malignant behavior observed in NOTCH3-expressing meningiomas, offering new insight into the biochemical vulnerabilities of these tumors."

Brain Cancer • Meningioma • Metabolic Disorders • Solid Tumor • CD36 • NOTCH3 • SCARB1

Stimulus-evoked increases in intracellular calcium promote susceptibility to ferroptosis in glioma cells (SNO 2025) - "Lastly, we performed viability screens to assess the effects of repetitive calcium bursts on susceptibility to the ferroptosis-inducing drug, RSL3...These findings reveal a mechanistic cascade from stimulus-evoked calcium increases to lipid peroxidation and ferroptosis-susceptibility in glioma. Current experiments in our lab are studying these effects in vivo, using physiologic stimulus-evoked neuronal activity to drive glioma calcium bursts and assess therapeutic efficacy when combined with pro-ferroptotic treatments."

Brain Cancer • Glioma • Solid Tumor • PDGFA

IDH1(R132H) inhibitors enhance the sensitivity of IDH1-mutant glioma to cysteine deprivation and ferroptosis. (SNO 2025) - "Finally, convection-enhanced delivery of RSL3 or the IDH1(R132H) inhibitor Ivosidenib, alone or in combination with dietary cysteine deprivation in vivo, significantly prolongs survival of IDH1-mutant tumor bearing mice. Our findings suggest that targeting cysteine metabolism and ferroptosis in addition to IDH1(R132H) inhibition provide promising therapeutic strategies for IDH1-mutant gliomas."

Brain Cancer • Glioma • Solid Tumor • GPX4 • IDH1 • PDGFA • TP53