elesclomol (STA-4783) / Madrigal Pharma - LARVOL DELTA

Combinatorial drug screen identifies therapeutic vulnerabilities of pancreatic cancer subtypes (ESMO-TAT 2026) - "decitabine, oxidative stress inducer elesclomol, and mitogen-activated protein kinase kinase (MEK) inh...rabusertib and AZD7762 ranked among the top combinations with AZD3965...adavosertib also sparked interest, as CHK1 and WEE1 inh... This systematic approach identifies candidate drug pairs for further preclinical testing and highlights translational starting points for developing personalized combination therapies to overcome resistance."

Colon Cancer • Colorectal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CHEK1 • SLC16A1

Cancer persister cells are sensitized to copper-mediated death (AACR 2026) - "Therefore, though disulfiram and elesclomol have failed to produce robust clinical benefit when paired with genotoxic chemotherapies or radiation in treatment-refractory tumors, no prior trials have applied either drug to targeted therapy treated tumors or minimal residual disease. Our observations support repurposing copper ionophores to target minimal residual disease in the context of oncogene-targeted therapy treatments."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AIFM2 • EGFR • GPX4

Cuproptosis induction in TP53-mutated acute myeloid leukemia (AACR 2026) - "In contrast, cytarabine, idarubicin, and venetoclax activity was substantially diminished in TP53-deficient cells, consistent with the known resistance of TP53-mutated AML to these standard therapies. Notably, combining low-dose elesclomol with the hypomethylating agent decitabine, which has established clinical efficacy in TP53-mutated AML, produced a synergistic increase in apoptosis in TP53-deficient AML cells.Together, these findings demonstrate that copper ionophores can bypass TP53-associated resistance to AML cell death by activating cuproptosis rather than relying on p53-dependent apoptotic pathways. The robust activity of copper ionophores across diverse TP53-deficient AML models, coupled with the enhanced efficacy observed in combination with decitabine, underscores cuproptosis induction as a promising therapeutic approach for TP53-deficient AML."

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

Selective induction of cuproptosis in vivo by a soluble Elesclomol analog (AACR 2026) - "Multiplexed imaging confirmed intratumoral aggregation of lipoylated proteins consistent with on-target cuproptosis induction. Together, these findings uncover a previously unrecognized role of FDX1-CYP coupling in regulating cuproptosis sensitivity and define a path toward biomarker-guided development of copper ionophore-based cancer therapies."

Preclinical • Oncology • CYP27A1 • FDX1

Targeting heat shock factor 1 in pancreatic ductal adenocarcinoma autophagy and iron-sulfur cluster protein stability (AACR 2026) - "The copper treatment also induces autophagy, yet whether copper-induced autophagy is regulated by HSF1 is not fully understood.Objective: The objective of this study is to study the role of HSF1 in copper-mediated loss of mitochondrial Fe-S cluster proteins and autophagy in PDAC cells.Methods and In PDAC cell lines MIA PaCa-2 and PANC-1, treatment with copper ionophore elesclomol-copper (ES-Cu) led to reduced protein levels of mitochondrial Fe-S cluster proteins, including aconitase 2 (ACO2), ferredoxin 1 (FDX1), and lipoic acid synthase (LIAS), but not mRNA expression...To investigate the mechanism of ES-Cu-mediated decrease of Fe-S cluster proteins, we pre-treated MIA PaCa-2 cells with hydroxychloroquine (CQ) along with ES-Cu... Our findings suggest that HSF1 protects PDAC cells from mitochondrial toxicity by maintaining the stability of Fe-S proteins under copper stress. Targeting HSF1 in combination with copper-based therapies may enhance treatment efficacy by..."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • FDX1 • HSF1 • LIAS • MAP1A

SIRT3 deacetylates STEAP4 to modulate cuproptosis sensitivity via mitochondrial metabolic reprogramming in HBV-related HCC. (PubMed, Cell Death Differ) - "Consequently, cells switch from the tricarboxylic acid (TCA) cycle respiration to glycolysis, reducing sensitivity to the copper ionophore elesclomol (ES)...HBx-mediated repression of SIRT3 disrupts STEAP4 deacetylation and mitochondrial targeting, fostering metabolic reprogramming and evasion of copper-induced cell death. The results provide a pre-clinical rationale for copper-directed combination strategies in HBV-associated HCC."

Journal • Hepatitis B • Hepatocellular Cancer • Infectious Disease • Oncology • Solid Tumor • SIRT3 • STEAP4

Dynamic PET Imaging of Elesclomol-Facilitated Copper Delivery in Ischemic Stroke Rats. (PubMed, ACS Omega) - "In ischemic SD rats, there was no significant difference in the 64Cu-ES uptake between the ischemic region and the contralateral side up to 24 h post-administration. These results provide direct evidence that ES can facilitate delivery of copper to the brain, supporting its potential as a therapeutic candidate for copper supplementation in ischemic stroke patients."

Journal • Preclinical • Cardiovascular • Ischemic stroke

The EZH2-NEAT1 epigenetic axis promotes cuproptosis sensitivity and modulates cancer cell migration in colorectal cancer. (PubMed, J Gastrointest Oncol) - "Using elesclomol-copper complex treatment, a cuproptosis model in HCT116 and RKO CRC cell lines was established...Tumors with elevated EZH2-NEAT1 expression may be particularly sensitive to copper-based therapies. This study establishes EZH2-NEAT1 expression as a potential biomarker for patient selection in cuproptosis-based cancer treatment, though the concurrent effects on tumor migration highlight complex therapeutic considerations for combination treatment strategies."

Journal • Colorectal Cancer • Oncology • Solid Tumor • DLAT • EZH2 • FDX1 • NEAT1

Therapeutic horizons of cuproptosis: bibliometric mapping of copper-dependent cell death research and its pharmacological implications. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Keyword and co-citation analyses revealed a thematic shift from foundational mechanistic studies toward prognostic modeling, copper ionophore exploration (e.g., elesclomol and disulfiram), immune-related analyses, and bioinformatics-driven patient stratification. The strong geographic concentration of publications and limited international collaboration highlight structural imbalances in knowledge production and the need for broader global validation. This bibliometric mapping clarifies the field's early developmental stage and identifies priorities for future research, including cross-regional collaboration, experimental standardization, and cautious advancement toward clinical application."

Journal • Oncology • FDX1

Elesclomol Promotes oxLDL-Mediated Foam Cell Formation and Cuproptosis in Macrophages. (PubMed, Biofactors) - "Mechanistically, the cytotoxic effects of Elesclomol were mediated through activation of the mitogen-activated protein kinase (MAPK) pathway and upregulation of metallothionein 2A (MT2A). Collectively, these findings underscore the critical role of cuproptosis in the pathogenesis of atherosclerosis and suggest that targeting this pathway may represent a promising therapeutic strategy for the disease."

Journal • Atherosclerosis • Cardiovascular • ABCA1 • ABCG1 • MT2A

Sanguinarine exerts anti-hepatocellular carcinoma activity by targeting FDX1 to induce FDX1/LIAS/DLAT/HSP70 axis-dependent cuproptosis. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Moreover, the combination of San with copper ionophores (Elesclomol-CuCl 2) exhibits synergistic effects in promoting cuproptosis...Surface plasmon resonance experiments and cellular thermal shift assay confirm that San strongly interacts with FDX1 and markedly enhances the thermostability of FDX1. In conclusion, our findings indicate that San substantially inhibits the progression of HCC by targeting FDX1/LIAS/DLAT/HSP70 axis-dependent cuproptosis."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • DLAT • FDX1 • LIAS

Amyloid beta 42 disrupts cardiac function in Alzheimer's disease mice via SLC31A1 upregulation-mediated cuproptosis. (PubMed, Basic Res Cardiol) - "Furthermore, Aβ1-42 acted synergistically with CuCl₂ or elesclomol-CuCl₂ to exacerbate cardiomyocyte death...Conclusion Aβ1-42 disrupts copper homeostasis by upregulating SLC31A1, thereby exacerbating myocardial cuproptosis and impairing cardiac function in AD. This novel mechanism highlights SLC31A1-mediated cuproptosis as a potential therapeutic target for preserving cardiac health in AD."

Journal • Preclinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Congestive Heart Failure • Heart Failure • Aβ42 • DLAT • SLC31A1

Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer. (PubMed, Nat Commun) - "Here, through a small-molecule compound screening, we identify elesclomol, a potent copper ionophore, which sensitizes BRCA-proficient ovarian cancer cells to PARPi by inhibiting activation of the ATR-CHK1 pathway...Importantly, we reveal a secondary metabolic vulnerability in PARPi-resistant ovarian cancer associated with de novo pyrimidine synthesis, suggesting that targeting this pathway as an effective strategy to eradicate drug-adaptive residual tumors and resistant patient-derived xenograft models following ATR and PARP co-inhibition. These findings propose de novo pyrimidine synthesis as an adaptive metabolic vulnerability that can be therapeutically targeted to overcome PARPi resistance in BRCA-proficient ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor • BRCA

Boosting Cuproptosis in Breast Cancer Therapy via Photodynamic Treatment With a New Liposome. (PubMed, FASEB Bioadv) - "In this study, we prepared a novel liposome loaded with the photosensitizer indocyanine Green (ICG) and the cuproptosis inducer elesclomol-Cu (ES-Cu) to examine the synergistic effects of photodynamic-cuproptosis treatment on BC...This investigation proved that PDT markedly augments the ES-Cu-induced cuproptosis in breast cancer cells, demonstrating a synergistic therapeutic effect. This synergistic effect presents a novel therapy approach for BC with substantial practical application potential."

Journal • Breast Cancer • Oncology • Solid Tumor

Regulation of the AKT/Wnt/β-catenin Pathway and Induction of Cuproptosis by Curcumin in Glioblastoma. (PubMed, J Vis Exp) - "A172 and U251 cells were treated with CUM, AKT inhibitor MK-2206, Wnt inhibitor LGK974, and Elsm-Cu (Elesclomol + CuCl2). In nude mice, CUM significantly reduced tumor growth, promoted cuproptosis, and inhibited AKT/Wnt/β-catenin axis activation. Our results indicate that CUM suppresses AKT/Wnt/β-catenin signaling, promotes cuproptosis, and interferes with GBM progression."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Clinically friendly smart hydrogel boosts cuproptosis and PD-L1 upregulation to enhance anti-tumor immunotherapy. (PubMed, Mater Today Bio) - "Herein, a temperature/pH dual-responsive composite hydrogel was developed to load Elesclomol-Cu (ES-Cu) and glucose oxidase (GOx) (ES-Cu&GOx@FFC)...Combined therapy experiments showed that the combination treatment of ES-Cu&GOx@FFC and αPD-L1 achieved more than 90 % tumor volume regression. In summary, this study provides new insights into the therapeutic role of cuproptosis in TNBC, and integrates cuproptosis, starvation therapy, CDT, and immunotherapy through smart responsive hydrogels, providing an innovative solution for the treatment of TNBC."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

m6A modification of ATOX1 inhibits acute myeloid leukemia progression by promoting cuproptosis. (PubMed, Cancer Res Commun) - "In this study, elesclomol (ES) or disulfiram (DSF)/Cu was used to induce cuproptosis, and bathocuproine disulfonic acid (BCS) was used to inhibit it. In vivo, the role of the ALKBH5-ATOX1 axis in AML progression has also been confirmed. In Conclusion, The demethylase ALKBH5 downregulates ATOX1 by reducing its m⁶A levels, thereby modulating cuproptosis in AML-a mechanism that offers potential novel insights and therapeutic targets for AML treatment."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ALKBH5

Punicalagin Targets FDX1 to Induce Cuproptosis for the Treatment of Gastric Cancer. (PubMed, IUBMB Life) - "Next, two gastric cancer cell lines (AGS, HGC27) were selected for in vitro experiments to assess the combined effects of PUN and the copper ionophore elesclomol (ES) (hereafter referred to as ES-Cu, representing the combination of ES and Cu2+)...In combination therapy strategies, PUN can work synergistically with chemotherapy drugs to suppress gastric cancer growth. Furthermore, PUN enhances its inhibitory effect on gastric cancer by working synergistically with cuproptosis through targeting FDX1."

Journal • Gastric Cancer • Metabolic Disorders • Oncology • Solid Tumor • DLAT • FDX1 • LIAS

Elesclomol Diminishes Redox Imbalance in Peripheral Tissues of Mblac1 Knockout Mice. (PubMed, J Biophotonics) - "Optical metabolic imaging reveals Mblac1 as a key regulator of systemic redox balance and supports ES as a potential therapy for Cu-linked metabolic dysfunctions."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Metabolic Disorders

Targeting SLC7A11 sensitizes colorectal cancer cells to elesclomol-Cu-induced cuproptosis via the GSH-GPX4 axis. (PubMed, Biochem Biophys Res Commun) - "SLC7A11 knockdown regulates intracellular redox balance through the GSH-GPX4 axis, thereby promoting cellular cuproptosis. Targeting SLC7A11 can enhance the sensitivity of CRC cells to copper ionophores and may represent a novel therapeutic strategy to enhance cuproptosis of CRC cells."

Journal • Colorectal Cancer • Oncology • Solid Tumor • GPX4 • SLC7A11

Copper modulates cell fate through the PLK1-FOXO3a-β-catenin signaling pathway by differentially regulating cuproptosis and EMT. (PubMed, Apoptosis) - "In contrast, co-treatment with Cu and copper ionophore elesclomol (Cu-ES) triggered cuproptosis, a unique copper-dependent form of cell death, accompanied by mitochondrial dysfunction, dihydrolipoamide S-acetyltransferase aggregation, and ATP depletion. The PLK1 inhibitor BI-2536 recapitulated the effects of Cu-ES and exhibited synergistic activity when combined with Cu-ES, enhancing both cell death and EMT suppression. These findings highlight a novel regulatory mechanism of EMT through copper signaling and support copper-based combination therapies as a promising approach to simultaneously inhibit tumor growth and metastasis in colorectal cancer."

Journal • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • DLAT • FOXO3 • ITK • PLK1

LRPPRC-Driven Oxidative Phosphorylation Is Associated with Elesclomol-Induced Cuproptosis in Ovarian Cancer. (PubMed, Int J Mol Sci) - "This inhibition collectively diminishes the expression and activity changes in complex IV, induces mitochondrial dysfunction, and promotes cuproptosis in ovarian cancer. This study further demonstrates that inhibiting the oxidative phosphorylation complex IV can enhance copper-induced cell death in ovarian cancer."

Journal • Metabolic Disorders • Oncology • Ovarian Cancer • Solid Tumor • ATP7B • DLAT • FDX1 • LIAS • LIPT1 • LRPPRC

Feeding-Triggered Seizures in a Newborn with AP1S1-Related MEDNIK Syndrome: Expanding the Phenotype of a Hyper-Rare Disease. (PubMed, J Clin Med) - "We describe her clinical course and the zinc acetate therapeutic experience. We also reviewed the literature focusing on clinical manifestations (especially neurological), brain neuroimaging and the symptom evolution of patients with AP1S1-related MEDNIK syndrome and discuss possible future therapeutic attempts."

Journal • Atopic Dermatitis • CNS Disorders • Dermatology • Epilepsy • Immunology • Mental Retardation • Metabolic Disorders • Otorhinolaryngology • Pain • Psychiatry • Rare Diseases • Vitiligo

FDX1-mediated cuproptosis promotes cholestatic liver injury exacerbated by taurocholic acid-enhanced copper accumulation. (PubMed, Cell Death Discov) - "In vitro, copper chloride/elesclomol-induced DLAT monomer reduction and oligomerization alongside impaired lipoylation...Cholestasis-induced copper overload drives liver injury via taurocholic acid-exacerbated and FDX1-mediated cuproptosis. Our findings propose TTM and SAG as therapeutic candidates and reveal complex FDX1 regulatory roles, suggesting novel approach for managing cholestatic liver injury."

Journal • Cholestasis • Hepatology • Liver Failure • DLAT • FDX1 • LIAS

High TERF2 expression is associated with poor prognosis and its suppression attenuates progression in acute myeloid leukemia. (PubMed, Transl Cancer Res) - "TERF2 knockdown induced apoptosis, suppressed cell proliferation, and downregulated the E2F pathway, while simultaneously enhancing cuproptosis susceptibility, as evidenced by reduced half-maximal inhibitory concentration (IC50) values of the elesclomol-copper (ES-Cu)...Downregulation of TERF2 inhibits the AML cell proliferation, induces apoptosis, and modulates cuproptosis sensitivity possibly via the E2F-mediated pathway. Targeting TERF2 not only inhibits proliferation but also unlocks cuproptosis as a therapeutic vulnerability, offering a potential strategy for AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • IL2RG • TERF2