ML210 / Bayer, University of Sydney, Broad Institute - LARVOL DELTA

Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations (Nature) - "We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. However, most strikingly, mitochondrial remodeling was evident, persisting into a therapy-resistant state. The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase (GPX4) inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS."

Preclinical • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

ProSLeM: A Novel Computational Platform to Accelerate Synthetic Lethality-Based Treatments for Prostate Cancer (LCC 2026) - "Consistent with this, SPOP-mutant LNCaP cells exhibited heightened sensitivity to GPX4 inhibitors (ML210, RSL3). ProSLeM reveals a genotype-linked SL landscape in PCa and pinpoints a glutathione–ferroptosis vulnerability in SPOP-mutant disease, nominating sorafenib as a precision therapeutic."

Synthetic lethality • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • GPX4 • RB1 • SLC3A2 • SPOP • TP53

An Engineered Nanovesicles-Based Lysosome-Targeting Protein Degradation Platform (NV-TACs) for Cancer Immunotherapy. (PubMed, J Am Chem Soc) - "Notably, by incorporation of a therapeutic payload (ML210), NV-TACs simultaneously exhibited targeted protein degradation and ML210-mediated ferroptosis through payload delivery capacity. Both in anti-PD-1-responsive and -resistant tumor models, NV-TACs demonstrated significant therapeutic efficacy without obvious systemic toxicity. The platform of NV-TACs paves new avenues for developing linker-free, modular, and bioinspired targeted protein degradation platforms."

Journal • Oncology • Targeted Protein Degradation • PD-L1

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

Unidirectional synergy between ferroptosis and apoptosis reveals a novel therapeutic strategy for refractory AML (ASH 2025) - "Given that both apoptosis and ferroptosis are regulated by mitochondriain AML cells, we sought to explore the molecular crosstalk between these two distinct forms of cell death.To test whether ferroptosis bypasses apoptotic resistance, we first treated venetoclax (VEN)-resistantAML cells including BAX/BAK double-knockout (DKO) AML cells with the selective GPX4 inhibitor ML210.ML210 effectively induced cell death in these models, confirming that ferroptosis involves a distinct,apoptosis-independent pathway...Consistently, combined treatment with GPX4inhibition and VEN significantly reduced peripheral leukemic burden in a patient-derived xenograftmouse model established from an R/R AML case previously treated with decitabine and VEN...Invivo, VEN followed by doxycycline-inducible GPX4 knockdown significantly reduced leukemic burden andprolonged the survival in a xenograft mouse model...Synergistic AML cell death caused by dual induction of mitochondrial ferroptosis and..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • ACSL4 • AIFM2 • CASP3 • CD34 • GPX4

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

PRDX1 depletion predisposes to ferroptosis through inhibiting the cAMP pathway in B-cell acute lymphoblastic leukemia. (PubMed, Cancer Gene Ther) - "Ferroptosis was induced in B-ALL cells using erastin...PRDX1 knockdown further reduced the viability of B-ALL cells treated with the ferroptosis activator ML210, and treatment with the ferroptosis inhibitor liproxstatin-1 significantly reversed the suppressive effect of PRDX1 knockdown on xenograft tumor growth. Mechanically, PRDX1 deletion triggered ferroptosis in B-ALL cells by inhibiting the cAMP pathway. PRDX1 deficiency modulates ferroptosis in B-ALL cells by blocking the cAMP pathway, which offer a novel perspective on the pathogenesis of B-ALL."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • ACSL4 • GPX4 • MT-CO2 • PRDX1

Role of ferroptosis-related GPX4 signaling in the fusion of human trophoblast cells. (PubMed, Sci Rep) - "To address the impact of ferroptosis signaling on syncytialization, forskolin-stimulated trophoblast BeWo cells were treated with GPX4 inhibitors RSL3, ML-210, or erastin...These effects were suppressed by deferoxamine, an iron chelator, and ferrostatin-1, a lipid peroxidation inhibitor, both of which significantly reduced hCGβ expression...Inhibition of the ER stress sensors IRE1α and ATF6 attenuated hCGβ expression, implicating these pathways in the regulation of syncytialization. Collectively, these findings suggest that ferroptosis-related lipid peroxidation and iron signaling contribute to the regulation of trophoblast fusion, potentially physiological role in placental development."

Journal • ATF6 • GPX4 • KEAP1

Molecular Interactions between Mitochondrial Ferroptosis and Apoptosis Pathways in Acute Myeloid Leukemia (ASH 2024) - "Results : We evaluated the anti-AML efficacy of dual induction of apoptosis and ferroptosis utilizing venetoclax (Ven) and ML210, a specific GPX4 inhibitor, as apoptosis and ferroptosis inducers, respectively...This synergism was also recapitulated in doxycycline-inducible GPX4 knockdown cells, supporting the on-target effects of pharmacologic GPX4 inhibition...Conclusion : Mitochondrial ferroptosis exhibits molecular interactions with apoptosis pathways in AML : ferroptosis induces CytC release in a BAX/BAK-independent manner, while apoptosis sensitizes AML cells to LP possibly by affecting mitochondrial lipid and oxidative metabolism. Targeting the ferroptosis-apoptosis interactions could evolved into a novel therapeutic strategy for AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • CD34 • GPX4

Mitophagy As a Novel Cell-Protective Mechanism Against Mitochondrial Ferroptosis in Acute Myeloid Leukemia (ASH 2023) - " We demonstrate that a selective GPX4 inhibitor ML210 as well as GPX4 knockdown induces ferroptosis, defined by iron- and lipid-peroxidation-dependence, in AML cell lines and primary AML samples, regardless of venetoclax resistance or genetic features including TP53 mutations. Our study revealed that ferroptosis in AML cells causes mitochondrial protein aggregation and that mitophagy is induced in ferroptosis-persistent AML cells as a cell-protective mechanism against ferroptosis. This provides novel mechanistic insights into mitochondrial ferroptosis in AML, suggesting the therapeutic potential of co-targeting mitophagy in ferroptosis-based therapy. Further studies are in progress to elucidate the molecular mechanisms involved as well as the in vivo efficacy and safety of the combinatorial treatment."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • GPX4 • TP53

Targeting Lipid Droplet Biogenesis to Enhance Ferroptosis in Acute Myeloid Leukemia (ASH 2024) - "We first confirmed that the exogenous supplement of PUFA (Linoleic acid) significantly enhanced ferroptosis in AML cells treated with the GPX4 inhibitor ML210, while monounsaturated fatty acid (MUFA, Oleic acid) suppressed GPX4 inhibition-induced ferroptosis, as expected...These findings suggest a novel therapeutic strategy for AML by targeting lipid metabolism to potentiate ferroptosis. Further investigation into the molecular underpinnings of the synergy, in vivo validations, and the development of specific DGAT inhibitors will be critical for translating these findings into clinical applications."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • GPX4

Metabolic Determinants of Ferroptosis in B-Cell Lymphoma (ASH 2024) - "Background and Significance : Approaches for targeted elimination of B-cells as the root-cause of disease have been highly effective in the treatment of B-cell lymphoma (rituximab, ibrutinib)...This was the case for multiple classes of ferroptosis inducers, including GPX4 inhibitors (RSL3, ML162, ML210), the cysteine-glutamate antiporter (system xc-, SLC7A11) inhibitor Erastin, and the iron oxidizer and GPX4 inactivator FINO2...This likely reflects the intrinsic dependency of B-cell lymphomas on iron import and PUFA-metabolism, at the cost of increased vulnerability to ferroptosis. Furthermore, our CRISPR screens performed with the ferroptosis inducers RSL3, Erastin, and FINO2 revealed phosphatidylcholine synthesis (FLVCR1, PCYT1A) and lipid membrane remodelling (ATP8B2) as central mechanistic targets in B-cell lymphomas."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ACSL3 • ACSL4 • BCL2 • GPX4 • MYC • SLC7A11

GPX4 Inhibition Enhances the Pro-Oxidant and ER Stress Effects of Tempol in Colon and Gastric Cancer Cell Lines. (PubMed, Curr Issues Mol Biol) - "These findings demonstrate that ML210 potentiates Tempol's pro-oxidant pressure by targeting GPX4, selectively amplifying H2O2 accumulation and ER stress engagement without collapsing global redox balance. This study provides mechanistic rationale for redox-proteostasis co-targeting in gastric and colon cancers and establishes a foundation for in vivo validation."

Journal • Preclinical • Colon Cancer • Colorectal Cancer • Gastric Cancer • Oncology • Solid Tumor • ATF6 • GPX4 • HSPA5

Delivery of a GPX4 Inhibitor by SN38 Prodrug Nanoassemblies for Amplified Antitumor Efficacy Based on Ferroptotic Chemotherapy. (PubMed, ChemMedChem) - "In the CT26 mouse model, ML210-loaded prodrug nanoassemblies demonstrated superior antitumor effects. The strategy-using prodrug as "carriers" for ferroptosis inducers-offers a promising approach for synergistic antitumor therapy."

Journal • Oncology • GPX4

Inhibition of de novo Lipogenesis through Acly and FASN Sensitizes PDAC to RT and Ferroptosis (ASTRO 2025) - "72 hours treatment with ACLY inhibitor BMS-303141(ACLYi; PK-EC50 14.0 uM, 7160c2-EC50 58uM, Panc-01-EC50 18uM, AsPC-1-EC50 40uM) or FASN inhibitor TVB-2640(FASNi; PK-EC50 24.4uM) resulted in decreased cell viability...Finally, we examined the ability of ACLY and FASN inhibition to sensitize to ferroptosis induction with GPX4 inhibitor ML-210... Lipid synthesis is stimulated in PDAC cells following RT, resulting in altered expression of numerous lipid species. Inhibition of lipogenesis enzymes ACLY and FASN reduces cell viability and can sensitize to RT. This sensitivity to upstream ACLY inhibition, but not downstream FASN inhibition, can be reversed by adding back acetate."

Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • APOE • FASN • GPX4

Dual Induction of Mitochondrial Ferroptosis and Apoptosis in Acute Myeloid Leukemia (SOHO 2025) - " AML cells were treated with ML210, a selective GPX4 inhibitor, and venetoclax (Ven). Mitochondrial ferroptosis exhibits paradoxical molecular interactions with apoptosis pathways in AML: GPX4 inhibition suppresses apoptosis, whereas BCL-2 inhibition enhances ferroptosis. Sequential induction of apoptosis followed by ferroptosis maximizes ferro-apoptosis and may provide a promising strategy for relapsed/refractory AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • GPX4

Activation of the Nrf2/HO-1/GPX4 pathway by cGAMP Mitigates oxidative stress and ferroptosis in ischaemic stroke. (PubMed, Biochem Pharmacol) - "Pharmacological inhibition of Nrf2 using ML-385 or GPX4 with ML-210 completely abrogated these protective effects, thereby confirming pathway specificity. These findings establish cGAMP as a novel dual modulator of redox homeostasis and ferroptosis in ischemic stroke pathophysiology."

Journal • Cardiovascular • CNS Disorders • Ischemic stroke • GPX4

TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy. (PubMed, Biochim Biophys Acta Mol Cell Res) - "Our results indicate that TXNIP is a key player in ferroptotic pathway, as its deletion conferred resistance to classic ferroptosis-inducing agents (erastin, RSL3, and ML210), while TXNIP overexpression increased their susceptibility to ferroptosis. Our findings suggest that TXNIP acts as a positive regulator of ferroptosis by modulating autophagy and iron availability. Targeting TXNIP might hold promise in developing drugs for diseases involving the ferroptotic pathway."

Journal • Review • CNS Disorders • Metabolic Disorders • Oncology • GPX4 • NCOA4 • TXNIP

Synergistic Induction of Ferroptosis in Acute Myeloid Leukemia by Modulating Intracellular Lipidomic Remodeling (SOHO 2025) - " We found that exposure to linoleic acid (a PUFA), sensitized AML cells to ferroptosis induced by the GPX4 inhibitor ML210, whereas exposure to oleic acid (a monounsaturated fatty acid) suppressed ferroptosis... These lines of evidence provide a preclinical proof-of-concept therapeutic strategy for AML by manipulating LD biogenesis and cellular PUFAs to synergistically enhance ferroptosis."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • GPX4

Diversity-Oriented Synthesis toward the Discovery of Ferrocenophane-Appended GPX4 Inhibitors as Potent Ferroptosis Inducers with Drug Likeness. (PubMed, J Med Chem) - "ML210-ansaFc exhibited robust tumor growth suppression in 3D spheroid models, coupled with favorable drug-like properties, highlighting its potential as a therapeutic agent for intractable cancers. This work could pave the way for the development of metallocene-based chemotypes with diverse spatial configurations for the treatment of multiple diseases."

Journal • Oncology • GPX4

PERTURBATIONS OF ANTIOXIDANT METABOLISM REVEAL REDOX-REGULATED PATHWAYS ESTABLISHING SURVIVAL REQUIREMENTS AND VULNERABILITIES OF AML (EHA 2025) - "To evaluate the effect of different compounds perturbing cellular antioxidant system (buthionine sulfoximine, auranofin, ezatiostat and ML-210) on the proliferation of leukemic cells we used multiple AML cell lines (ML-2, NOMO-1, SHI-1, Monomac-6 and OCI-M2 cells) and real-time monitored their proliferation using live-cell imaging methods. Collectively, we determined the nodes of the leukemia antioxidant system that are critical for cell survival and identified changes in protein abundance and oxidation state triggered by their perturbation. Targeting such proteins and their pathways may represent an efficient strategy to improve the therapeutical outcomes of AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • GPX4 • GSTP1

A NOVEL ROLE FOR TRANSCRIPTION FACTOR NFE2 IN REGULATING REDOX RESPONSES AND CHEMOTHERAPY RESISTANCE IN ACUTE MYELOID LEUKEMIA (EHA 2025) - "Following cytarabine, parthenolide and ML-210 treatment, HEL and HL-60 cells were assessed for cell viability and apoptosis induction using CellTiter-Glo and AnnexinV/PI assays.We integrated ChIP-, ATAC- and RNA-seq analyses to investigate NFE2-driven transcriptional changes in CB3 cells. Increased NFE2 activity promotes leukemogenesis both in patients and in murine models. Here, we present the first comprehensive multi-omics profiling of NFE2 function, revealing a novel role for the transcription factor in regulating glutathione levels and protection from oxidative stress. We propose a model in which NFE2 promotes AML initiation and persistence by conferring resistance to ROS-mediated cell death during both disease initiation and therapy."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ANXA5 • GPX4

Inhibition of NAD-GPx4 axis and MEK triggers ferroptosis to suppress pancreatic ductal adenocarcinoma. (PubMed, Mol Ther) - "The combined application of GPx4 and Mitogen-activated protein kinase kinase (MEK) inhibitors, namely ML210 and trametinib, respectively, reduced lethality and tumor-like phenotypes in these flies. Notably, this combination treatment synergistically suppressed the proliferation of human PDAC cells and their corresponding xenografts in mice by inducing ROS accumulation, which triggered ferroptosis. These results suggest that inducing ferroptosis could represent a promising therapeutic strategy for PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • GPX4

Physiologic regulation of lipid oxidation and ferroptosis by vitamin E, high-density lipoprotein and scavenger receptor class B type 1 (AACR 2025) - "Ferroptosis was induced using ML210 and erastin. We reveal a tunable cellular redox axis whereby HDLs containing α-toc target SR-B1 to reduce PL-OOH and prevent ferroptosis. Accordingly, this work reveals that the α-toc / HDL/ SR-B1 axis of ferroptosis prevention must be accounted for when targeting ferroptosis in vivo."

B Cell Lymphoma • Clear Cell Renal Cell Carcinoma • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • APOB • GPX4