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

Targeted Lifetime Probe Enables Quantitative FLIM Mapping of Lipid Droplet Polarity Remodeling under Copper-Induced Oxidative Stress. (PubMed, Anal Chem) - "In living cells, LDP-Pol resolved LD polarity-associated microenvironmental changes during H2O2-induced oxidative stress and CuCl2/elesclomol-induced copper stress, while dual-color super-resolution imaging confirmed its compatibility with live-cell organelle tracking and LD-mitochondria contact analysis. In tumor models, LDP-Pol enabled tissue-level FLIM visualization of heterogeneous lipid polarity landscapes under copper-induced stress. These results establish a lifetime-based strategy for probing LD microenvironmental remodeling associated with oxidative and metal-induced cellular perturbation."

Journal • Metabolic Disorders • Oncology

Glutathione reductase deficiency potentiates the immunogenicity of ferroptosis and cuproptosis via amplified reactive oxygen species accumulation and cGAS-STING pathway activation. (PubMed, J Hematol Oncol) - "GSR represents a key molecular node connecting and modulating ferroptosis and cuproptosis through redox regulation. Targeting GSR amplifies ROS-mediated immunogenic cell death, triggers cGAS-STING activation in cancer cells, and enhances the efficacy of cancer immunotherapy, providing a promising redox-based therapeutic strategy."

IO biomarker • Journal • Metabolic Disorders • Oncology • HMGB1

Targeting cuproptosis uncovers metabolic vulnerabilities in glioblastoma stem cells (ECP 2026) - "Cuproptosis-related transcriptional profiles define biologically distinct GSC subgroups with differential sensitivity to elesclomol. These findings suggest that a cuproptosis-primed metabolic state may contribute to tumor aggressiveness while simultaneously creating a possible therapeutic vulnerability. This study provides a strong rationale for the development of novel agents targeting this pathway in GBM."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • LIPT1

Bifunctional Ionophores for Cuproptosis Activation: Dual Targeting of Copper and Fe-S Protein Homeostasis. (PubMed, J Med Chem) - "They coordinate copper via hydroxyquinoline and efficiently transport copper into cancer cells, with HDQ-Me achieving an efficacy comparable to that of the clinical copper ionophore elesclomol (ES)...HDQ-mediated copper loading triggers cuproptosis hallmarks, DNA damage, and ATP collapse, generating a synergistic lethality. This work establishes HDQs as bifunctional tools that cotarget copper and Fe-S protein homeostasis, validating a convergent therapeutic strategy against resilient cells."

Journal • Oncology

Targeting cuproptosis uncovers metabolic vulnerabilities in glioblastoma stem cells (ECP 2026) - "Cuproptosis-related transcriptional profiles define biologically distinct GSC subgroups with differential sensitivity to elesclomol. These findings suggest that a cuproptosis-primed metabolic state may contribute to tumor aggressiveness while simultaneously creating a possible therapeutic vulnerability. This study provides a strong rationale for the development of novel agents targeting this pathway in GBM."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • LIPT1

Distinct Effects of Copper Ionophores on Intracellular Copper and Cell Viability in Wild-Type and CTR1-Deficient SH-SY5Y Cells. (PubMed, ACS Omega) - "In this study, we investigated the effects of selected copper-binding compoundsα-lipoic acid (LA), elesclomol (ES), disulfiram (DSF), thiourea (TU), and triapine (3-AP)on copper uptake and cytotoxicity in SH-SY5Y wild-type (WT) and CTR1-deficient (CTR1-/-) cells. Overall, our results demonstrate that copper ionophores can enhance intracellular copper levels dependently and independently of CTR1, with distinct effects on cell viability. Among the tested compounds, LA and DSF showed a favorable profile by increasing copper levels while maintaining low cytotoxicity, highlighting their potential for modulating cellular copper homeostasis."

Journal • Alzheimer's Disease • CNS Disorders

DIXDC1 Promotes Lymphatic Metastasis and Resistance to Cuproptosis in Bladder Cancer Through Mediating DLAT. (PubMed, Adv Sci (Weinh)) - "Importantly, DIXDC1 shields BCa cells from copper-induced DLAT oligomerization and confers marked resistance to Elesclomol-Cu (ES-Cu)-triggered cuproptosis. Depletion of DIXDC1 profoundly sensitizes tumors to cuproptosis in vivo. Collectively, our study unveils the DIXDC1-DLAT axis as a pivotal regulator that coordinately drives metastatic progression and suppresses copper-induced cell death, offering a promising therapeutic target for advanced BCa."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CCNE2 • DIXDC1 • DLAT

FGFR4 suppresses antitumor immunity and cuproptosis by disrupting CYLD-mediated stabilization of STING and FDX1. (PubMed, Cancer Lett) - "Combination therapy with lenvatinib and elesclomol synergistically suppressed tumor growth in immunocompetent mouse models. Across patient cohorts, FGFR4-high/STING-low tumors were associated with inferior responses to anti-PD-1-based therapy. Together, these findings establish FGFR4 as a central regulator of antitumor immunity and cuproptosis and highlight combined FGFR4 inhibition and cuproptosis induction as a promising therapeutic strategy."

Journal • Oncology • Targeted Protein Degradation • FDX1 • FGFR4 • STING

Inhibition of PINK1/Parkin-mediated mitophagy enhances the susceptibility of breast cancer to cuproptosis. (PubMed, Oncogene) - "In this study, we induced cuproptosis of breast cancer cells using Elesclomol (ES) and assessed changes in mitochondrial reactive oxygen species, mitochondrial membrane potential, and oxygen consumption rate. The combination of dichloroacetate (DCA) and ES exhibited a synergistic antitumor effect without significant tissue damage on the brain, heart, liver, and kidneys in subcutaneous mouse xenograft models. Collectively, our findings reveal that inhibiting PINK1/Parkin-mediated mitophagy enhances the sensitivity of breast cancer to cuproptosis, offering a novel combined treatment strategy for breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • DLAT

Copper homeostasis and cuproptosis: New perspectives on the diagnosis and treatment of metabolic diseases. (PubMed, J Trace Elem Med Biol) - "Copper chelators including tetrathiomolybdate and merestinib are primary agents for metabolic tissue preservation, whereas ionophores such as elesclomol are restricted to oncology, with lipid nanoparticle-based delivery platforms essential to overcome the blood-brain barrier challenge, as underscored by the neurological worsening documented in D-penicillamine-treated Wilson disease patients. The interplay between cuproptosis and ferroptosis, sharing GSH depletion but diverging at lipoylated protein aggregation versus glutathione peroxidase 4 (GPX4)-dependent lipid peroxidation, suggests dual-pathway inhibition may be necessary. Future priorities include validation of the metabolic threshold hypothesis, β-cell-specific knockout studies, standardised DLAT oligomerisation diagnostics, tissue-targeted copper modulator delivery, and integration of cuproptosis biomarkers with multi-omics and artificial intelligence for clinically stratified precision medicine."

Journal • Review • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Movement Disorders • Obesity • Oncology • Type 2 Diabetes Mellitus • ATP7B • DLAT • FDX1 • GPX4 • LIAS • LIPT1

GSH-responsive self-assembled nanoplatform synergistically enhances cuproptosis through metabolic reprogramming and oxidative stress amplification. (PubMed, Mater Today Bio) - "Here, we developed a tumor microenvironment-responsive nanoparticle platform (PEMA) co-loading an MPC1 (mitochondrial pyruvate carrier 1) overexpression plasmid and the copper ionophore Elesclomol to establish a synergistic "metabolic reprogramming-oxidative stress amplification" strategy...In vivo, PEMA treatment induced substantial tumor regression in xenograft models without detectable systemic toxicity. This study establishes a novel therapeutic paradigm that integrates metabolic targeting with oxidative stress potentiation to overcome therapeutic resistance in solid tumors."

Journal • Kidney Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • DLAT • FDX1

C1R suppresses hepatocellular carcinoma cell aggressiveness through promoting HIF-1α degradation and modulating cuproptosis-related protein expression. (PubMed, Int Immunopharmacol) - "C1R is a shared cuproptosis-associated regulator in HBV infection and HCC. The data support a model in which C1R reduces aggressive phenotypes of HCC cells partly through destabilizing HIF-1α and reshaping copper-responsive processes."

Journal • Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Liver Failure • Oncology • Solid Tumor • Targeted Protein Degradation • DLAT • DLST • FDX1 • HIF1A

Dihydrolipoamide dehydrogenase promotes hepatocellular carcinoma progression and modulates cuproptosis-dependent cell death. (PubMed, Funct Integr Genomics) - "Importantly, depletion of DLD heightened susceptibility to cuproptosis, which was further augmented by elesclomol to intensify cell death, decrease FDX1 expression, and deplete ATP levels, but effects that were reversed by tetrathiomolybdate. In conclusion, DLD promotes HCC progression through regulating cuproptosis sensitivity, serving as both a prognostic biomarker and a potential therapeutic target for enhancing cuproptosis-based therapies in HCC."

Journal • Fibrosis • Hepatocellular Cancer • Immunology • Oncology • Solid Tumor • DLD • FDX1

ATP7A Orchestrates Tumor Progression and Cuproptosis in Hepatocellular Carcinoma via the LINC02038-miR-506-3p Regulatory Circuit. (PubMed, J Biochem Mol Toxicol) - "Sensitivity to cuproptosis was assessed by measuring intracellular copper/ROS levels and IC50 of elesclomol-Cu...Our findings reveal that the LINC02038/miR-506-3p/ATP7A axis played a crucial oncogenic role in HCC by driving tumor progression and modulating cuproptosis. This axis represents a promising prognostic biomarker and a potential therapeutic target for HCC intervention."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Thoracic Cancer • ATP7A • DLAT • FDX1 • LINC02038 • LIPT1 • MIR506

Metal-dependent regulated cell death: Molecular architecture and translational frontiers. (PubMed, Imeta) - "To bridge the persistent knowledge gap between foundational metallobiology and clinical application, we evaluated a bidirectional therapeutic framework: exploiting synthetic lethality and metabolic gating via clinical inducers (e.g., sorafenib, elesclomol) to selectively eliminate therapy-resistant malignancies while deploying targeted pathway inhibitors and systemic agonists (e.g., dipyridamole, omaveloxolone) to limit pathological tissue degeneration in ischemic and neurodegenerative disorders. Specifically, we highlighted the integration of single-atom catalysts, stimuli-responsive nanomedicines, and biomimetic carriers engineered to spatiotemporally confine catalytic oxidative flux. Finally, we examined the systemic immunological consequences of targeted metal dysregulation, detailing how metal-induced immunogenic cell death and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway hyperactivation reshape immunosuppressive microenvironments..."

Journal • Review • CNS Disorders • Oncology • CGAS • STING

LINC02207 suppresses breast cancer progression by promoting cuproptosis through NFAT5 regulation. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "These findings reveal a critical tumor-suppressive role of LINC02207 mediated through NFAT5-dependent regulation of cuproptosis and suggest that LINC02207 may serve as a promising therapeutic target in breast cancer."

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

Evaluating the prognostic value of cuproptosis-related genes and characterizing PDE3B's role in gastric cancer: integrative bioinformatics analysis and experimental validation. (PubMed, J Gastrointest Oncol) - "Elesclomol-CuCl2 (ES-Cu) triggered canonical cuproptosis features in gastric cancer cells, and PDE3B expression was downregulated during this process. Notably, the inhibition of PDE3B significantly potentiated ES-Cu induced cuproptosis. We characterized the landscape of CRG dysregulation in gastric cancer, verified that ES-Cu exhibited a significant cytotoxic effect on gastric cancer, and elucidated the pivotal role of PDE3B in gastric cancer."

Journal • Gastric Cancer • Oncology • Solid Tumor • MAP2K2

Cuproptosis tracker: Visualizing organelle dynamics with a dual-targeted fluorescent probe. (PubMed, J Pharm Anal) - "Dual fluorescence channel imaging associated SO2 fluctuations with Mito-LDs targeting, revealing the interaction between LDs-Mito during Cu2+ and elesclomol (ES) induced apoptosis. In addition to imaging, MLR-based test strips and hydrogels can achieve rapid (<1 min) on-site SO2 detection. As a dual-organelle tracer for cuproptosis, MLR overcomes single-target probe limitations, offering a transformative platform to analyze spatiotemporal organelle dynamics for advancing diagnostic tools development."

Journal • Metabolic Disorders

The CpG island methylator phenotype defines an immune-cold and therapy-resistant subtype of cutaneous melanoma. (PubMed, Front Immunol) - "Drug sensitivity modeling identified multiple candidate compounds, including elesclomol and Wnt pathway inhibitors...CIMP defines a clinically relevant melanoma subtype characterized by epigenetic remodeling, genomic instability, and an immune-poor tumor microenvironment, and is associated with poor prognosis and reduced benefit from immunotherapy. These findings suggest that therapeutic resistance in CIMP+ melanoma is multifactorial and highlight potential avenues for targeted intervention."

IO biomarker • Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • ARID2 • BRAF • IFNG • NRAS

MKRN1 suppresses cuproptosis in colorectal cancer through ubiquitin-dependent regulation of SLC31A1. (PubMed, Biol Proced Online) - "In summary, MKRN1 suppresses copper-induced cell death in colorectal cancer by promoting the ubiquitination and proteasomal degradation of the copper transporter SLC31A1, thus limiting copper accumulation and mitochondrial toxicity. This mechanism confers resistance to copper-induced cell death and facilitates tumor progression, establishing the MKRN1/SLC31A1 axis as a promising therapeutic target."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • DLAT • SLC31A1

Glutathione-depleting self-immolative nanoparticles boost cuproptosis-driven metalloimmunotherapy for triple-negative breast cancer. (PubMed, J Nanobiotechnology) - "The polymer backbone covalently integrates an L-buthionine sulfoximine prodrug to inhibit glutathione biosynthesis, and the nanoparticle matrix encapsulates an elesclomol-copper complex to promote intratumoral copper accumulation...Notably, combination with anti-PD-1 checkpoint blockade yields synergy, significantly enhancing the ICB responsiveness of TNBC and producing improved therapeutic efficacy. Overall, this study demonstrates that EsCu@NPs enable coordinated cuproptosis and immune reprogramming, expanding ICB efficacy and supporting a translatable neoadjuvant strategy in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8

Cuproptosis and prostate cancer: from molecular mechanisms and microenvironment remodeling to precision therapy. (PubMed, Front Oncol) - "Therapeutically, copper ionophores such as elesclomol and disulfiram/copper, and copper-depleting approaches such as chelators, are discussed as investigational strategies rather than near-clinical solutions. Particular attention is given to toxicity, narrow therapeutic windows, negative or inconclusive clinical data, the absence of validated companion diagnostics in PCa, and the need for patient-selection biomarkers based on copper handling, FDX1/lipoylation status, and mitochondrial dependency. Finally, we outline the experimental and translational studies required before cuproptosis-directed interventions can be rationally tested in advanced PCa."

IO biomarker • IO Companion diagnostic • Journal • PD(L)-1 companion diagnostic • Review • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • DLAT • FDX1

DNA-damage-targeting copper nanoparticles induce cuproptosis for enhanced cancer radiotherapy. (PubMed, Mater Today Bio) - "Here, we report a first-of-its-kind copper-doped metal-organic framework nanoplatform, based on a ZIF-8 framework and loaded with the copper ionophore elesclomol, to concurrently induce cuproptosis and amplify radiotherapy...We demonstrate that Cu-MOF@ELS strongly induces cuproptosis in tumor cells and significantly boosts radiotherapeutic efficacy in vitro and in vivo, with treated mice showing pronounced tumor regression and minimal systemic toxicity. Our work pioneers a novel therapeutic paradigm by integrating cuproptosis induction with radiotherapy, establishing Cu-MOF@ELS as a groundbreaking radiosensitizer that exploits metabolic cell-death mechanisms to overcome tumor radioresistance."

Journal • Melanoma • Metabolic Disorders • Oncology • Solid Tumor

p53-associated regulation of COX17 enhances elesclomol-induced copper-associated cytotoxicity and suppresses gastric cancer growth. (PubMed, Front Immunol) - "COX17 may enhance copper accumulation, oxidative stress, tumor-cell-death-associated changes, and angiogenesis-related phenotypic inhibition. Further studies using canonical cuproptosis markers, copper chelator rescue experiments, additional gastric cancer cell lines with different p53 backgrounds, and clinical validation are required to confirm the translational significance of this pathway."

Journal • Gastric Cancer • Oncology • Solid Tumor • ATP7A • SLC31A1

Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression. (PubMed, bioRxiv) - "Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling...Mitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • SLC25A3